COMT Inhibiting Methods and Compositions

ABSTRACT

This invention relates to compounds, pharmaceutical compositions and their use for treating neuropsychiatric and neurodegenerative disorders. In particular, the invention relates to inhibitors of catechol-O-methyltransferase and their use as therapeutics for central nervous system disease.

NIH GRANT

This invention was made with government support under R01MH107126awarded by National Institutes of Health. The government has certainrights in the invention.

FIELD OF THE INVENTION

This invention relates to compounds, pharmaceutical compositions andtheir use for treating neuropsychiatric and neurodegenerative disorders.In particular, the invention relates to inhibitors ofcatechol-O-methyltransferase and their use as therapeutics for centralnervous system disease.

BACKGROUND

Cognitive disorders are observed in many neurological and psychiatricdisorders, be they neurodegenerative (e.g. Parkinson's disease,Alzheimer's disease), neurodevelopmental (e.g. schizophrenia, autismspectrum disorders) or the consequence of other etiology.

Parkinson's disease is a progressive neurodegenerative disorder(synucleopathy) diagnosed on the basis of characteristic motordisturbances, asymmetry of symptoms onset and response to levodopa(Litvan et al., 2003). Lewy bodies, neurofibrillary tangles and plaquesare observed in nigral, limbic and neocortical regions. Thesedegenerations are supposed to affect catecholaminergic (dopamine andnorepinephrine) and cholinergic neurotransmission. In particular, animportant part of cognitive deficits (executive function and workingmemory) have been related to a decreased prefrontal dopaminergicsignaling in non-demented patients (Nandakumar et al., 2013).

Schizophrenia is the result of a complex series of neurodevelopmental orother changes that lead to impaired information processing in the brain(Marenco and Weinberger 2000). No single genetic change, aberrantprotein function, or visible brain lesion has been demonstrated to leadto schizophrenia, and many different genetic and environmental changesare linked to increased disease risk (Fatemi and Folsom 2009). Whilemany neurochemical signaling systems, such as the various monoamines,NMDA, and GABA, are likely to play a role in the etiology ofschizophrenia (Pickard 2011), many pathways seem to converge on aberrantdopamine signaling as a final common pathway that leads to many of theobserved symptoms (Howes and Kapur 2009).

With regard to the cognitive impairment, for which there is currently notreatment, patients with schizophrenia show significant deficits inspecific cognitive domains, especially executive function, workingmemory, and episodic memory. Cognitive domains which are dysfunctioningin these two disorders are complex functions involving manyneurotransmitters and brain regions; however, dopamine signaling in thedorsolateral prefrontal cortex (DLPFC) has been shown to play a criticalrole in these processes (Goldman-Rakic, Castner et al. 2004). Oneapproach to rectifying cortical dopamine neurotransmission is to takeadvantage of the differential modes of clearance of dopamine from thedifferent brain regions. In the midbrain, there is extensive expressionof the dopamine transporter (DAT), which is thought to be primarilyresponsible for dopamine clearance from the synapse (Ciliax, Heilman etal. 1995). In contrast, cortical regions exhibit only low levels of DATexpression, and dopamine is cleared primarily by enzymatic catabolism ofdopamine, with a contribution from the norepinephrine transporter (NET)(Yavich, Forsberg et al. 2007; Kaenmaki, Tammimaki et al. 2010). Theprimary enzymes responsible for dopamine catabolism in the prefrontalcortex (“PFC”) are monoamine oxidase (MAO) andcatechol-O-methyltransferase (“COMT”).

Beyond Parkinson's and schizophrenia, inhibition of COMT may be usefulin a number of neuro-psychiatric conditions, including ADHD,obsessive-compulsive disorder, alcoholism, depression, bipolar disorder(Lachman, Papolos et al. 1996), as well as age-associated cognitivesymptoms, impulse control disorders, including compulsive gambling,sexual behavior, and other compulsive destructive behaviors. The role ofCOMT in dopamine metabolism in the brain make it an especially importanttarget for improvement of cognition (Apud and Weinberger 2007).

Additionally, COMT inhibitors have shown utility in Parkinson's diseasetreatment, due to the role of COMT in metabolizing the dopamineprecursor L-DOPA, which is given to Parkinson's disease patients toboost the levels of dopamine in the brain (Bonifacio, Palma et al.2007). Since dopamine cannot cross the blood-brain barrier, L-DOPA isadministered in its place and is transported into the brain andsubsequently processed to dopamine. The percentage of exogenouslyadministered L-DOPA that reaches the brain is 1%, and this low brainavailability necessitates a high dose, which leads to peripheral sideeffects (Nutt and Fellman 1984). The primary enzymes responsible fordopamine metabolism are aromatic amino acid decarboxylase (AAAD) andCOMT. Therefore, extensive efforts have been undertaken to developpotent and selective inhibitors of both enzymes. Carbidopa is an AAADinhibitor now routinely given with L-DOPA, reducing the efficaciousL-DOPA dose by 60-80% (Nutt, Woodward et al. 1985). Addition of a COMTinhibitor further decreases the variability of L-DOPA exposure, and abrain-penetrating COMT inhibitor could also increase brain dopaminelevels.

Inhibitors of COMT have been developed for treatment of Parkinson'sdisease (Learmonth, Kiss et al. 2010). Notably, the nitrocatecholscaffold has been exploited to provide the clinically used drugstolcapone and entacapone (Bonifacio, Palma et al. 2007). While they areeffective in blocking peripheral COMT activity, entacapone hasnegligible brain penetration, and tolcapone has low but measurablelevels in the brain (Russ, et al. 1999). Compounds with improved brainpenetration should have greater efficacy for Parkinson's disease, aswell as have utility for other psychiatric and neurological conditionssuch as cognitive impairment in schizophrenia. Despite the earlyclinical success achieved with tolcapone, the drug has been associatedwith serious liver injury, including three deaths, and requires strictliver function monitoring (Olanow and Watkins 2007). Thus, therisk-benefit profile for tolcapone prevents its widespread deployment,and new, inhibitors of COMT are needed, especially those that are activein the brain. Borchardt disclosed a series of non-nitrocatecholquinoline COMT inhibitors, but these compounds had weak potency(Borchardt, Thakker et al. 1976).

Accordingly, there remains a need for potent inhibitors of COMT andmethods of using the same to treat central nervous system disorders.

SUMMARY OF THE INVENTION

The present invention provides compounds, pharmaceutical compositionsand methods of treating or preventing neurological or psychiatricdisorders for which inhibiting COMT provides a therapeutic effect.

The present invention also provides methods of treating or preventing aneurological or psychiatric disorder, or treating symptoms associatedwith a neurological or psychiatric disorder, and in particular suchdisorders for which inhibiting COMT provides a therapeutic effect. In aparticular embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds according to formulaI, or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo; iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₅ is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀ alkyl orC₁-C₁₀ cycloaklyl, optionally substituted with one or more groupsselected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄ alkyl;C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl;alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄ alkyl; and

Y is (CR₆R₇)_(n), wherein n is from 0-3, and R₆ and R₇ are independentlyselected from hydrogen; C₁-C₆ alkyl; C₃-C₅ cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆ and R₇ may alsocome together to form a C₃-C₆ cycloalkyl; or when R₅ is phenyl, one ofR₆ or R₇ comes together with R₅ to form a bicycle.

Also provided herein are COMT-inhibiting compounds in accordance withformula I, or pharmaceutically acceptable salts thereof:

Also provided herein are pharmaceutical compositions comprising theCOMT-inhibiting compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The terms below, when used herein, have the following meanings unlessindicated otherwise.

As used in this specification and the appended claims, the singularforms “a”, “an” and “the” include plural references unless the contentclearly dictates otherwise.

When any variable (e.g. aryl, heterocycle, R¹, etc.) occurs more thanone time in any constituent, its definition on each occurrence isindependent at every other occurrence.

“Alkyl” refers to a saturated hydrocarbon chain. Such hydrocarbon chainsmay be branched or linear. “Alkyl” groups may be substituted by one ormore substituents selected from halogen, amido, aryl or alkoxy.Particular alkyl groups according to the present invention includemethyl, trifluoromethyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl,1-ethylpropyl, 3-methylpentyl, octyl and the like.

The term “C₁-C₆” (for example), or “C₁₋₆”, includes, for this example,alkyls containing 6, 5, 4, 3, 2, or 1 carbon atom(s).

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarbonradical, including bridged, fused, or spiro cyclic compounds, preferablyhaving 3 to 8 carbon atoms. Nonlimiting examples of “C₃-C₆ cycloalkyl”groups according to the present invention are cyclopropyl, cyclopentyl,cyclohexyl and the like.

The compounds of the present invention may contain one or moreasymmetric centers and may thus occur as racemates, racemic mixtures,single enantiomers, diastereomeric mixtures, and individualdiastereomers.

It will be understood that, as used herein, references to the compoundsof the present invention are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds or inother synthetic manipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salts” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids. When the compound of the presentinvention is acidic, its corresponding salt can be conveniently preparedfrom pharmaceutically acceptable non-toxic bases, including inorganicbases and organic bases. Salts derived from such inorganic bases includealuminum, ammonium, calcium, copper (ic and ous), ferric, ferrous,lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc andthe like salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamme, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, and tromethamine.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.

A “pharmaceutically acceptable excipient” or “pharmaceuticallyacceptable carrier” refers to an excipient that can be included in thecompositions of the invention and that causes no significant adversetoxicological effects to the subject or patient to which the compositionis administered. “Pharmacologically effective amount,” “physiologicallyeffective amount,” and “therapeutically effective amount” are usedinterchangeably herein to mean the amount of an active agent present ina pharmaceutical preparation that is needed to provide a desired levelof active agent and/or conjugate in the bloodstream or in the targettissue. The precise amount will depend upon numerous factors, e.g., theparticular active agent, the components and physical characteristics ofpharmaceutical preparation, intended patient population, patientconsiderations, and the like, and can readily be determined by oneskilled in the art, based upon the information provided herein andavailable in the relevant literature.

The term “patient” refers to a living organism suffering from or proneto a condition that can be prevented or treated by administration of anactive agent as described herein, and includes both humans and animals.In one embodiment, the patient is a human patient.

The term “mammal” “mammalian” or “mammals” includes humans, as well asanimals, such as dogs, cats, horses, pigs and cattle.

Without being bound by theory, the administration of compounds accordingto the invention in an “effective amount” or “therapeutically effectiveamount” provides a concentration of the compound that functions as aCOMT inhibitor sufficient to inhibit the effect of the COMT enzymecomplex.

“Treating” or “treatment” of a disease state includes: 1) inhibiting thedisease state, i.e., arresting the development of the disease state orits clinical symptoms; 2) attenuating the disease state, i.e. reducingthe number or intensity of one or more symptoms associated with thedisease state, such that one or more symptoms is reduced but may, or maynot be completely eliminated; and/or 3) relieving the disease state,i.e., causing temporary or permanent regression of the disease state orits clinical symptoms.

“Prevent” or “preventing” a disease state includes: preventing thedisease state, i.e. causing the clinical symptoms of the disease statenot to develop in a subject that may be exposed to or predisposed to thedisease state, but does not yet experience or display symptoms of thedisease state.

All patents, patent applications and publications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

II. Methods

One aspect of the invention is a method of treating or preventing aneurological or psychiatric disorder, or treating symptoms associatedwith a neurological or psychiatric disorder, and in particular suchdisorders for which inhibiting COMT provides a therapeutic effect.Without being bound by theory, the therapeutic effect provided accordingto the invention is achieved by inhibiting the metabolism ofcatecholamines by COMT. Accordingly, in an aspect of the invention, theinvention provides methods of treating and/or preventing disease forwhich inhibiting degradation of catecholamines such as, for example,dopamine, norepinephrine or L-dihydroxyphenylalanine (L-DOPA) provides abeneficial therapeutic effect.

In another aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds of formula I. Thesemethods comprise administering to a subject in need thereof an effectiveamount of a COMT-inhibiting compound in accordance with formula I, or apharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₅ is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀ alkyl orC₁-C₁₀ cycloaklyl, optionally substituted with one or more groupsselected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄ alkyl;C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl;alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄ alkyl; and

Y is (CR₆R₇)_(n), wherein n is from 0-3, and R₆ and R₇ are independentlyselected from hydrogen; C₁-C₆ alkyl; C₃-C₅ cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆ and R₇ may alsocome together to form a C₃-C₆ cycloalkyl; or when R₅ is phenyl, one ofR₆ or R₇ comes together with R₅ to form a bicycle.

In another aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds of formula Ia. Thesemethods comprise administering to a subject in need thereof an effectiveamount of a COMT-inhibiting compound in accordance with formula Ia, or apharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₅ is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀ alkyl orC₁-C₁₀ cycloaklyl, optionally substituted with one or more groupsselected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄ alkyl;C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl;alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄ alkyl; and

Y is (CR₆R₇)_(n), wherein n is from 0-3, and R₆ and R₇ are independentlyselected from hydrogen; C₁-C₆ alkyl; C₃-C₅ cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; or when R₅ isphenyl, one of R₆ or R₇ comes together with R₅ to form a bicycle.

In another embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds of formula II. Thesemethods comprise administering to a subject in need thereof an effectiveamount of a COMT-inhibiting compound in accordance with formula II, or apharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

P, Q and R are each independently selected from CH and N;

R₁₀ can be at one or more positions on the ring, and at each occurrenceis independently selected from hydrogen; mono-, di-, or trihalomethyl;C₁-C₄ alkyl; C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy;aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄ alkyl; or R₁₀comes together with P, Q or R to form a bicycle; and

R₆ and R₇ are each independently selected from hydrogen; C₁-C₆ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; R₆ and R₇ may also come together to form a C₃-C₆ cycloalkyl; orone of R₆ or R₇ comes together with P to form a bicycle.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In still another particular embodiment,three of R₁, R₂, R₃ and R₄ are hydrogen. In yet another particularembodiment, R₁, R₂, R₃, R₄, R₆ and R₇ are each hydrogen.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen, and P, Q and R are all CH. In another preferred embodiment, Xis H; three of R₁, R₂, R₃ and R₄ are hydrogen; R₆ and R₇ are eachhydrogen and P, Q and R are all CH. In still another preferredembodiment, X is H; three of R₁, R₂, R₃ and R₄ are hydrogen; one of R₆or R₇ is hydrogen; and P, Q and Rare all CH.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula IIa, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

P, Q and R are each independently selected from CH and N;

R₁₀ can be at one more more positions on the ring, and at eachoccurrence is independently selected from hydrogen; mono-, di-, ortrihalomethyl; C₁-C₄ alkyl, C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano;nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R isC₁-C₄ alkyl; or R₁₀ comes together with P, Q or R to form a bicycle; and

R₆ and R₇ are each independently selected from hydrogen; C₁-C₆ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; or one of R₆ or R₇ comes together with P to form a bicycle.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In still another particular embodiment,three of R₁, R₂, R₃ and R₄ are hydrogen. In yet another particularembodiment, R₁, R₂, R₃, R₄, R₆ and R₇ are each hydrogen.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen, and P, Q and R are all CH. In another preferred embodiment, Xis H; three of R₁, R₂, R₃, R₄, R₆ and R₇ are each hydrogen and P, Q andR are all CH. In still another preferred embodiment, X is H; three ofR₁, R₂, R₃ and R₄ are hydrogen; one of R₆ or R₇ is hydrogen; and P, Qand R are all CH.

In another embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds of formula IIb.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting compound in accordance withformula IIa, or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

P is CH;

R₁₀ can be at one or more positions on the ring, and at each occurrenceis independently selected from hydrogen; mono-, di-, or trihalomethyl;C₁-C₄ alkyl; C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy;aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄ alkyl; or R₁₀comes together with P to form a bicycle; and

R₆ and R₇ are each independently selected from hydrogen; C₁-C₆ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; R₆ and R₇ may also come together to form a C₃-C₆ cycloalkyl; orone of R₆ or R₇ comes together with P to form a bicycle.

In a particular embodiment, Z is fluoro and X is H. In anotherparticular embodiment, R₁, R₂, R₃ and R₄ are hydrogen. In yet anotherparticular embodiment, R₁, R₂, R₃, R₄, R₆, R₇ are each hydrogen.

In a preferred embodiment, Z is fluoro and X is H and R₁, R₂, R₃, R₄, R₆and R₇ are hydrogen. In yet another preferred embodiment, X is H; R₁,R₂, R₃, R₄, R₆, R₇ and R₁₀ is selected from optionally substitutedphenyl or methyl.

In exemplary embodiments, a method of inhibiting COMT enzyme in asubject comprises administering one or more of the following compounds:

In another particular embodiment, the invention provides a method ofinhibiting COMT enzyme in a subject by administering compounds offormula III. These methods comprise administering to a subject in needthereof an effective amount of a COMT-inhibiting compound in accordancewith formula III, or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl; and

R₆, R₇, R₁₁ and R₁₂ are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, ortrihaloalkyl; and aryl; R₆ and R₇, R₁₁ and R₁₂, R₆ or R₇ and R₁₁ or R₁₂may also come together to form a C₃-C₆ cycloalkyl.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In yet another particular embodiment,R₁, R₂, R₃, R₄, R₆, R₇, R₁₁ and R₁₂ are each hydrogen.

In a preferred embodiment, X is H and R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen. In yet another preferred embodiment, X is H; R₁, R₂, R₃, R₄,R₆, R₇ and R₁₁ are hydrogen and R₁₂ is selected from phenyl or methyl.

In another particular embodiment, the invention provides a method ofinhibiting COMT enzyme in a subject by administering compounds offormula Ilia. These methods comprise administering to a subject in needthereof an effective amount of a COMT-inhibiting compound in accordancewith formula IIIa, or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl; and

R₆, R₇, R₁₁ and R₁₂ are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, ortrihaloalkyl; and aryl.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In yet another particular embodiment,R₁, R₂, R₃, R₄, R₆, R₇, R₁₁ and R₁₂ are each hydrogen.

In a preferred embodiment, X is H and R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen. In yet another another preferred embodiment, X is H; R₁, R₂,R₃, R₄, R₆, R₇ and R₁₁ are hydrogen and R₁₂ is selected from phenyl ormethyl. In exemplary embodiments, a method of inhibiting COMT enzyme ina subject comprises administering one or more of the followingcompounds:

In another embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds of formula IV. Thesemethods comprise administering to a subject in need thereof an effectiveamount of a COMT-inhibiting compound in accordance with formula IV, or apharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylakyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆, R₇, R₁₁, R₁₂, R₁₃ and R₁₄ are each independently selected fromhydrogen; C₁-C₄ alkyl; C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-,di-, or trihaloalkyl and aryl; R₆ and R₇, R₁₁ and R₁₂, R₁₃ and

R₁₄, R₆ or R₇ and R₁₁ or R₁₂, R₆ or R₇ and R₁₃ or R₁₄, R₁₁ or R₁₂ andR₁₃ or R₁₄ may also come together to form a C₃-C₆ cycloalkyl; and

R₁₅ and R₁₆ are each hydrogen or come together to form a ring.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In still another particular embodiment,R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃ and R₁₄ are each hydrogen.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂,R₁₃, R₁₄, R₁₅ and R₁₆ are hydrogen. In yet another preferred embodiment,X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₃ and R₁₄ are hydrogen; R₁₂ ismethyl; and R₁₅-R₁₆ form a dioxolane.

In another embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds of formula IVa.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting compound in accordance withformula IVa, or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylakyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆, R₇, R₁₁, R₁₂ R₁₃ and R₁₄ are each independently selected fromhydrogen; C₁-C₄ alkyl; C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-,di-, or trihaloalkyl and aryl; and

R₁₅ and R₁₆ are each hydrogen or come together to form a ring.

In exemplary embodiments, a method of inhibiting COMT enzyme in asubject comprises administering one or more of the following compounds:

In another embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds of formula V. Thesemethods comprise administering to a subject in need thereof an effectiveamount of a COMT-inhibiting compound in accordance with formula V, or apharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl; and

R₁₀ can be at one or more positions on the ring, and at each occurrenceis independently selected from the group consisting of hydrogen; mono-,di-, or trihalomethyl; C₁-C₄ alkyl; C₃-C₁₀ cycloalkyl; halo; heteroaryl;cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein Ris C₁-C₄ alkyl.

In a preferred embodiment, X is H; R₁, R₂, R₃, and R₄ are hydrogen; andR₁₀ is selected from hydrogen, C₁-C₄ alkyl and mono-, di- ortrihalomethyl. In a more specific embodiment, R₁₀ is hydrogen. In analternative specific embodiment, R₁₀ is methyl. In yet anotheralternative specific embodiment, R₁₀ is trifluoromethyl.

In another embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds of formula Va. Thesemethods comprise administering to a subject in need thereof an effectiveamount of a COMT-inhibiting compound in accordance with formula Va, or apharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl; and

R₁₀ can be at one or more positions on the ring, and at each occurrenceis independently selected from from the group consisting of hydrogen;mono-, di-, or trihalomethyl; C₁-C₄ alkyl; C₃-C₁₀ cycloalkyl; halo;heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and—NHC(O)R, wherein R is C₁-C₄ alkyl.

In a preferred embodiment, X is H; R₁, R₂, R₃, and R₄ are hydrogen; andR₁₀ is selected from hydrogen, C₁-C₄ alkyl and mono-, di- ortrihalomethyl. In a more specific embodiment, R₁₀ is hydrogen. In analternative specific embodiment, R₁₀ is methyl. In yet anotheralternative specific embodiment, R₁₀ is trifluoromethyl. In exemplaryembodiments, a method of inhibiting COMT enzyme in a subject comprisesadministering one or more of the following compounds:

In another embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds of formula VI. Thesemethods comprise administering to a subject in need thereof an effectiveamount of a COMT-inhibiting compound in accordance with formula VI or apharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

Y is (CR₆R₇)_(n), wherein n is from 0-3, and R₆ and R₇ are independentlyselected from hydrogen; C₁-C₆ alkyl; C₃-C₅ cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆ and R₇ may alsocome together to form a C₃-C₆ cycloalkyl Het is a heterocycle. Het maybe connected to the R₆/R₇ carbon at any position of the heterocycle,provided it provides proper valency. In particular embodiments, theheterocycle is aromatic. Examples of heteroaromatics include, but arenot limited to indole; 1H-pyrazole; benzothiazole; benzotriazole;quinoline; isoquinoline; quinoxaline; 5-chloro-1,3-dimethyl-1H-pyrazole;4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole;3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole;2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇, arehydrogen, and Het is selected from the group consisting of 1H-pyrazole;benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one;1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole;6-(p-tolyl)imidazo[2,1-b]thiazole; 2-phenylthiazole and3,5-dimethyl-1-phenyl-1H-pyrazole.

In another embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds of formula Via.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting compound in accordance withformula Via or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆ and R₇ are each independently selected from hydrogen; C₁-C₄ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; and Het is a heterocycle. Het may be connected to the R₆/R₇ carbonat any position of the heterocycle, provided it provides proper valency.In particular embodiments, the heterocycle is aromatic. Exemplaryheteroaromatics include, but are not limited to indole; 1H-pyrazole;benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one;1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole;6-(p-tolyl)imidazo[2,1-b]thiazole; 2-phenylthiazole and3,5-dimethyl-1-phenyl-1H-pyrazole.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇, arehydrogen, and Het is selected from the group consisting of 1H-pyrazole;benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one;1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole;6-(p-tolyl)imidazo[2,1-b]thiazole; 2-phenylthiazole and3,5-dimethyl-1-phenyl-1H-pyrazole.

In exemplary embodiments, a method of inhibiting COMT enzyme in asubject comprises administering one or more of the following compounds:

In another particular embodiment, the invention provides a method ofinhibiting COMT enzyme in a subject by administering compounds offormula VII. These methods comprise administering to a subject in needthereof an effective amount of a COMT-inhibiting compound in accordancewith formula VII, or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆ and R₇ are each independently selected from hydrogen; C₁-C₄ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; R₆ and R₇ may also come together to form a C₃-C₆ cycloalkyl; and

R₁₇ and R₁₈ are selected from C₁-C₄ alkyl or come together to form a5-10 membered cycloalkane, which can optionally be further substitutedwith C₁-C₈ alkyl or cycloalkyl.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇, arehydrogen, and R₁₇ and R₁₈ are methyl. In another preferred embodiment, Xis H; R₁, R₂, R₃, R₄, R₆ and R₇, are hydrogen, and R₁₇ and R₁₈ cometogether to form a 6, 7 or 8 membered cycloalkane, which is furthersubstituted with C₁-C₈ alkyl or cycloalkyl.

In another particular embodiment, the invention provides a method ofinhibiting COMT enzyme in a subject by administering compounds offormula Vila. These methods comprise administering to a subject in needthereof an effective amount of a COMT-inhibiting compound in accordancewith formula Vila, or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆ and R₇ are each independently selected from hydrogen; C₁-C₄ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; and

R₁₇ and R₁₈ are selected from C₁-C₄ alkyl or come together to form a5-10 membered cycloalkane, which can optionally be further substitutedwith C₁-C₈ alkyl or cycloalkyl.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇, arehydrogen, and R₁₇ and R₁₈ are methyl. In another preferred embodiment, Xis H; R₁, R₂, R₃, R₄, R₆ and R₇, are hydrogen, and R₁₇ and R₁₈ cometogether to form a 6, 7 or 8 membered cycloalkane, which is furthersubstituted with C₁-C₈ alkyl or cycloalkyl.

In exemplary embodiments, a method of inhibiting COMT enzyme in asubject comprises administering one or more of the following compounds:

In another aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering to a subject in need thereof aneffective amount of a compound selected from the following:

-   2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[4-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(4-fluorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[2-(benzotriazol-1-yl)ethyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[2-(benzotriazol-2-yl)ethyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-tert-butylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,4-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[4-(propan-2-yl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[4-(pyridin-3-yl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(4-ethylphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile-   2-(4-ethyl-3-nitrobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-ethylbutyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(3,5-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(cyclohexylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-cyclopropylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(cyclooctylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,5-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-{[1-(phenylsulfonyl)-1H-indol-2-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(3-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(3,5-difluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-methylbenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[(5-phenyl-1H-pyrazol-3-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-{[6-chloro-4-(1H-imidazol-4-yl)-3,4-dihydro-2H-chromen-8-yl]methyl}-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,3-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(1,3-benzothiazol-2-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[(4-oxo-4H-chromen-3-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1H-indazol-3-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-{[3-(thiophen-2-yl)-1H-pyrazol-4-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[(3-phenyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dimethoxybenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(4-phenoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[3-(1,3-benzodioxol-5-yl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[4-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[3-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,1,3-benzothiadiazol-5-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[2-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-{[6-(4-methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-chloro-4-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-difluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(4-bromo-2-chloro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chloro-4-cyclopropyl-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chlorophenyl)methyl]-7-hydroxy-3,3-dimethyl-1,4-dihydropyrido[1,2-a]pyrazin-8-one-   2-[(2,4-dichloro-5-nitro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[1-(2-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(4-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2,5-dichlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-{1-[4-(trifluoromethyl)phenyl]ethyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[1-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(3-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-chloro-2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2,6-dimethoxyphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[1-(2,3,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-{1-[2-(benzyloxy)phenyl]ethyl}-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylpentyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-phenyl-3,4-dihydro-2H-chromen-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(3-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[cyclopentyl(phenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[1-(3-methoxyphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(3-chloro-2,6-difluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2,5-dimethylphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(1,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylbutyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   4-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]benzonitrile-   3-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]benzonitrile-   N-{3-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]phenyl}acetamide-   2-[1-(2,5-difluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(4-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-hydroxy-1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2,2,2-trifluoro-1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylcyclopropyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-(2-fluoro-1-phenyl-ethyl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-(2,2-difluoro-1-phenyl-ethyl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-(1,3-benzothiazol-2-yl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-phenylcyclopropyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(5-quinolyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(3-phenyloxetan-3-yl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(3-methylphenyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[2-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   1,2-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-benzyl-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dichlorobenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   (1R)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   (1S)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dimethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   1-(4-fluorophenyl)-7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1-[3-(pyridin-3-yl)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-benzyl-7-hydroxy-3-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2,3-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   3-benzyl-2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-3-methyl-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-benzyl-7-hydroxy-3-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-benzyl-7-hydroxy-3-(2-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   9-chloro-2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   6-fluoro-7-hydroxy-2-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chlorophenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   9-chloro-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   9-chloro-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   9-bromo-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   9-bromo-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chlorophenyl)methyl]-7-hydroxy-9-iodo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   9-cyclopropyl-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one.

The compounds for use in the instant method may be selected from any oneor any combination of compounds designated 1-142 herein.

For use in the method, the compound or compounds of the presentinvention, described above, is typically provided as a pharmaceuticalcomposition wherein the compound or compounds is present in combinationwith a pharmaceutically acceptable carrier as described herein. Suchpharmaceutical compositions are also provided by this disclosure.

For use in the method, the compound(s) of the present invention,described above, may also be used in combination with another additionaltherapeutic agent.

The methods of the present invention may be used to treat or prevent aneurological or psychiatric disorder. In particular, exemplaryembodiments of the invention include methods of treating or preventingschizophrenia, major depression, a depressive phase of bipolar disorder,attention deficit disorder, attention deficit/hyperactivity disorder,substance dependency, or increased appetite associated with smokingcessation or antipsychotic use. Other significant indications includeage-associated cognitive symptoms, impulse control disorders, includingcompulsive gambling, sexual behavior, and other compulsive destructivebehaviors.

In addition to the psychiatric indications, the methods of the inventionmay also be used to treat neurological disorders. In one embodiment, themethod of the present invention comprises administering an effectiveamount of a compound described herein above in combination with L-DOPAfor treatment of Parkinson's disease. The compound can be administeredin combination with L-DOPA, concurrently or separately, with or withoutan aromatic L-amino acid decarboxylase inhibitor (AADC) such ascarbidopa, to prevent or inhibit COMT-mediated metabolism of L-DOPA.

III. Compounds

Also disclosed herein are the novel 7-hydroxy-tetrahydropyridopyrazinonederivatives described above which, preferably, are inhibitors ofcatechol O-methyltransferase (COMT) enzyme, and which are useful in thetreatment or prevention of neurological or psychiatric disorders ordiseases in which COMT is involved. The compounds of the invention arecharacterized by their activity to inhibit the enzyme COMT. In preferredembodiments, the compounds of the present invention are effective toinhibit the enzyme COMT, in an assay which determines the inhibitoryconcentration (IC₅₀) for the conversion of the methyl donor S-adenosylmethionine to S-adenosyl homocysteine (SAH) as described herein, with apIC₅₀ superior or equal to 4.5. In increasingly preferred embodiments,the pIC₅₀ as so determined is superior or equal to 6.0. In a morepreferred embodiment, the pIC₅₀ as so determined is superior or equal to7.0.

The ability of compounds within the scope of this invention to inhibitthe activity of catechol-O-methyltransferase (COMT) may be determined bymethods known to those in the art for measuring COMT inhibition. Onemethod for measuring COMT activity uses a homogenous time-resolvedfluorescent (HTRF) assay (Lina et al, 2012; kit from CisBio, Codolet,France). This assay measures the production of-S-adenosyl homocysteine(SAH) from the methyl donor S-adenosyl methionine. Using this assaypreferred compounds of the invention have a pIC₅₀ superior or equal to4.5. In increasingly preferred embodiments, the pIC₅₀ as so determinedis superior or equal to 6.0. In a more preferred embodiment, the pIC₅₀as so determined is superior or equal to 7.0.

Provided herein are COMT-inhibiting compounds in accordance with formulaI, or pharmaceutically acceptable salts thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₅ is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀ alkyl orC₁-C₁₀ cycloaklyl, optionally substituted with one or more groupsselected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄ alkyl;C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl;alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄ alkyl; and

Y is (CR₆R₇)_(n), wherein n is from 0-3, and each R₆ and R₇ areindependently selected from hydrogen; C₁-C₆ alkyl; C₃-C₅ cycloalkyl;C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl;

R₆ and R₇ may also come together to form a C₃-C₆ cycloalkyl; or when R₅is phenyl, one of R₆ or R₇ comes together with R₅ to form a bicycle.

In another embodiment are COMT-inhibiting compounds in accordance withformula Ia, or pharmaceutically acceptable salts thereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₅ is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀ alkyl orC₁-C₁₀ cycloaklyl, optionally substituted with one or more groupsselected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄ alkyl;C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl;alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄ alkyl; and

Y is (CR₆R₇)_(n), wherein n is from 0-3, and each R₆ and R₇ areindependently selected from hydrogen; C₁-C₆ alkyl; C₃-C₅ cycloalkyl;C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; or when R₅is phenyl, one of R₆ or R₇ comes together with R₅ to form a bicycle.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula II, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

P, Q and R are each independently selected from CH and N;

R₁₀ can be at one more positions on the ring, and at each occurrence isindependently selected from hydrogen; mono-, di-, or trihalomethyl;C₁-C₄ alkyl, C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy;aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄ alkyl; or R₁₀comes together with P, Q or R to form a bicycle; and

R₆ and R₇ are each independently selected from hydrogen; C₁-C₆ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; R₆ and R₇ may also come together to form a C₃-C₆ cycloalkyl; orone of R₆ or R₇ comes together with P to form a bicycle.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In still another particular embodiment,three of R₁, R₂, R₃ and R₄ are hydrogen. In yet another particularembodiment, R₁, R₂, R₃, R₄, R₆ and R₇ are each hydrogen.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen, and P, Q and R are all CH. In another preferred embodiment, Xis H; three of R₁, R₂, R₃, R₄, R₆ and R₇ are each hydrogen and P, Q andR are all CH. In still another preferred embodiment, X is H; three ofR₁, R₂, R₃ and R₄ are hydrogen; one of R₆ or R₇ is hydrogen; and P, Qand R are all CH.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula IIa, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

P, Q and R are each independently selected from CH and N;

R₁₀ can be at one more more positions on the ring, and at eachoccurrence is independently selected from hydrogen; mono-, di-, ortrihalomethyl; C₁-C₄ alkyl, C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano;nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R isC₁-C₄ alkyl; or R₁₀ comes together with P, Q or R to form a bicycle; and

R₆ and R₇ are each independently selected from hydrogen; C₁-C₆ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; or one of R₆ or R₇ comes together with P to form a bicycle.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In still another particular embodiment,three of R₁, R₂, R₃ and R₄ are hydrogen. In yet another particularembodiment, R₁, R₂, R₃, R₄, R₆ and R₇ are each hydrogen.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen, and P, Q and R are all C. In another preferred embodiment, Xis H; three of R₁, R₂, R₃, R₄, R₆ and R₇ are each hydrogen and P, Q andR are all C. In still another preferred embodiment, X is H; three of R₁,R₂, R₃ and R₄ are hydrogen; one of R₆ or R₇ is hydrogen; and P, Q and Rare all CH.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula IIb, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

P is CH;

R₁₀ can be at one more positions on the ring, and at each occurrence isindependently selected from hydrogen; mono-, di-, or trihalomethyl;C₁-C₄ alkyl; C₃-C₁₀ cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy;aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄ alkyl; or R₁₀comes together with P to form a bicycle; and

R₆ and R₇ are each independently selected from hydrogen; C₁-C₆ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; R₆ and R₇ may also come together to form a C₃-C₆ cycloalkyl; orone of R₆ or R₇ comes together with P to form a bicycle.

In a particular embodiment, Z is fluoro and X is H. In anotherparticular embodiment, R₁, R₂, R₃ and R₄ are hydrogen. In yet anotherparticular embodiment, R₁, R₂, R₃, R₄, R₆, R₇ are each hydrogen.

In a preferred embodiment, Z is fluoro and X is H and R₁, R₂, R₃, R₄, R₆and R₇ are hydrogen. In yet another preferred embodiment, X is H; R₁,R₂, R₃, R₄, R₆, R₇ and R₁₀ is selected from optionally substitutedphenyl or methyl.

In exemplary embodiments, a compound is selected from the following:

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula III, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl; and

R₆, R₇, R₁₁ and R₁₂ are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, ortrihaloalkyl; and aryl; R₆ and R₇; R₁₁ and R₂; R₆ or R₇ and R₁₁ or R₁₂may also come together to form a C₃-C₆ cycloalkyl.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In yet another particular embodiment,R₁, R₂, R₃, R₄, R₆, R₇, R₁₁ and R₁₂ are each hydrogen.

In a preferred embodiment, X is H and R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen. In yet another preferred embodiment, X is H; R₁, R₂, R₃, R₄,R₆, R₇ and R₁₁ are hydrogen and R₁₂ is selected from phenyl or methyl.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula IIIa, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl; and

R₆, R₇, R₁₁ and R₁₂ are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, ortrihaloalkyl; and aryl.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In yet another particular embodiment,R₁, R₂, R₃, R₄, R₆, R₇, R₁₁ and R₁₂ are each hydrogen.

In a preferred embodiment, X is H and R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen. In yet another another preferred embodiment, X is H; R₁, R₂,R₃, R₄, R₆, R₇ and R₁₁ are hydrogen and R₁₂ is selected from phenyl ormethyl.

In exemplary embodiments, a compound is selected from the following:

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula IV, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆, R₇, R₁₁, R₁₂ R₁₃ and R₁₄ are each independently selected fromhydrogen; C₁-C₄ alkyl; C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-,di-, or trihaloalkyl and aryl; R₆ and R₇, R₁₁ and R₁₂, R₁₃ and R₁₄, R₆or R₇ and R₁₁ or R₁₂, R₆ or R₇ and R₁₃ or R₁₄, R₁₁ or R₁₂ and R₁₃ or R₁₄may also come together to form a C₃-C₆ cycloalkyl; and

R₁₅ and R₁₆ are each hydrogen or come together to form a ring.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In still another particular embodiment,R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃ and R₁₄ are each hydrogen.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂,R₁₃, R₁₄, R₁₅ and R₁₆ are hydrogen. In yet another preferred embodiment,X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₃ and R₁₄ are hydrogen; R₁₂ ismethyl; and R₁₅-R₁₆ form a dioxolane.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula IVa, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆, R₇, R₁₁, R₁₂, R₁₃ and R₁₄ are each independently selected fromhydrogen; C₁-C₄ alkyl; C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-,di-, or trihaloalkyl; and aryl; and

R₁₅ and R₁₆ are each hydrogen or come together to form a ring.

In a particular embodiment, X is H. In another particular embodiment,R₁, R₂, R₃ and R₄ are hydrogen. In still another particular embodiment,R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃ and R₁₄ are each hydrogen.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂,R₁₃, R₁₄, R₁₅ and R₁₆ are hydrogen. In yet another another preferredembodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₃ and R₁₄ arehydrogen; R₁₂ is methyl; and R₁₅-R₁₆ form a dioxolane.

In exemplary embodiments, a compound is selected from the following:

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula V, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl; and

R₁₀ can be at one or more positions on the ring, and at each occurrenceis independently selected from the group consisting of hydrogen; mono-,di-, or trihalomethyl; C₁-C₄ alkyl; C₃-C₁₀ cycloalkyl; halo; heteroaryl;cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein Ris C₁-C₄ alkyl.

In a preferred embodiment, X is H; R₁, R₂, R₃, and R₄ are hydrogen; andR₁₀ is selected from hydrogen, C₁-C₄ alkyl and mono-, di- ortrihalomethyl. In a more specific embodiment, R₁₀ is hydrogen. In analternative specific embodiment, R₁₀ is methyl. In yet anotheralternative specific embodiment, R₁₀ is trifluoromethyl.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula Va, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl; and

R₁₀ can be at one or more positions on the ring, and at each occurrenceis independently selected from from the group consisting of hydrogen;mono-, di-, or trihalomethyl; C₁-C₄ alkyl; C₃-C₁₀ cycloalkyl; halo;heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and—NHC(O)R, wherein R is C₁-C₄ alkyl.

In a preferred embodiment, X is H; R₁, R₂, R₃, and R₄ are hydrogen; andR₁₀ is selected from hydrogen, C₁-C₄ alkyl and mono-, di- ortrihalomethyl. In a more specific embodiment, R₁₀ is hydrogen. In analternative specific embodiment, R₁₀ is methyl. In yet anotheralternative specific embodiment, R₁₀ is trifluoromethyl.

In exemplary embodiments, a compound is selected from the following:

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula VI, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

Y is (CR₆R₇)_(n), wherein n is from 0-3, and R₆ and R₇ are independentlyselected from hydrogen; C₁-C₆ alkyl; C₃-C₅ cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆ and R₇ may alsocome together to form a C₃-C₆ cycloalkyl

Het is a heterocycle. Het may be connected to the R₆/R₇ carbon at anyposition of the heterocycle, provided it provides proper valency. Inparticular embodiments, the heterocycle is aromatic. Examples ofheteroaromatics include, but are not limited to indole; 1H-pyrazole;benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one;1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole;6-(p-tolyl)imidazo[2,1-b]thiazole 2-phenylthiazole and3,5-dimethyl-1-phenyl-1H-pyrazole.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇, arehydrogen, and Het is selected from the group consisting of 1H-pyrazole;benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one;1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole;6-(p-tolyl)imidazo[2,1-b]thiazole 2-phenylthiazole and3,5-dimethyl-1-phenyl-1H-pyrazole.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula Via, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆ and R₇ are each independently selected from hydrogen; C₁-C₄ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; and Het is a heterocycle. Het may be connected to the R₆/R₇ carbonat any position of the heterocycle, provided it provides proper valency.In particular embodiments, the heterocycle is aromatic. Exemplaryheteroaromatics include, but are not limited to indole; 1H-pyrazole;benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one;1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole;6-(p-tolyl)imidazo[2,1-b]thiazole 2-phenylthiazole and3,5-dimethyl-1-phenyl-1H-pyrazole.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇, arehydrogen, and Het is selected from the group consisting of 1H-pyrazole;benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one;1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole;6-(p-tolyl)imidazo[2,1-b]thiazole 2-phenylthiazole and3,5-dimethyl-1-phenyl-1H-pyrazole.

In exemplary embodiments, a compound is selected from the following:

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula VII, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro.

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆ and R₇ are each independently selected from hydrogen; C₁-C₄ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; R₆ and R₇ may also come together to form a C₃-C₆ cycloalkyl; and

R₁₇ and R₁₈ are selected from C₁-C₄ alkyl or come together to form a5-10 membered cycloalkane, which can optionally be further substitutedwith C₁-C₈ alkyl or cycloalkyl.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen, and R₁₇ and R₁₈ are methyl. In another preferred embodiment, Xis H; R₁, R₂, R₃, R₄, R₆ and R₇ are hydrogen, and R₁₇ and R₁₈ cometogether to form a 6, 7 or 8 membered cycloalkane, which is furthersubstituted with C₁-C₈ alkyl or cycloalkyl.

In another embodiment, the invention provides COMT-inhibiting compoundsin accordance with formula Vila, or pharmaceutically acceptable saltsthereof:

wherein:

X is selected from hydrogen; chloride; bromide and cyclopropyl;

R₁ and R₂ are each independently selected from hydrogen; C₁₋₄ alkyl;aryl; substituted aryl; arylalkyl and heterocycle;

R₃ and R₄ are each independently selected from hydrogen; C₁-C₄ alkyl;aryl and arylalkyl;

R₆ and R₇ are each independently selected from hydrogen; C₁-C₄ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono-, di-, or trihaloalkyl; andaryl; and

R₁₇ and R₁₈ are selected from C₁-C₄ alkyl or come together to form a5-10 membered cycloalkane, which can optionally be further substitutedwith C₁-C₈ alkyl or cycloalkyl.

In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆ and R₇ arehydrogen, and R₁₇ and R₁₈ are methyl. In another preferred embodiment, Xis H; R₁, R₂, R₃, R₄, R₆ and R₇ are hydrogen, and R₁₇ and R₁₈ cometogether to form a 6, 7 or 8 membered cycloalkane, which is furthersubstituted with C₁-C₈ alkyl or cycloalkyl.

In exemplary embodiments, a compound is selected from the following:

In particular embodiments, COMT-inhibiting compounds of the presentinvention are selected from the following:

-   2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[4-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(4-fluorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[2-(benzotriazol-1-yl)ethyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[2-(benzotriazol-2-yl)ethyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-tert-butylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,4-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[4-(propan-2-yl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[4-(pyridin-3-yl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(4-ethylphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile-   2-(4-ethyl-3-nitrobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-ethylbutyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(3,5-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(cyclohexylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-cyclopropylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(cyclooctylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,5-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-{[1-(phenylsulfonyl)-1H-indol-2-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(3-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(3,5-difluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-methylbenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[(5-phenyl-1H-pyrazol-3-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-{[6-chloro-4-(1H-imidazol-4-yl)-3,4-dihydro-2H-chromen-8-yl]methyl}-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,3-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(1,3-benzothiazol-2-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[(4-oxo-4H-chromen-3-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1H-indazol-3-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-{[3-(thiophen-2-yl)-1H-pyrazol-4-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[(3-phenyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dimethoxybenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(4-phenoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[3-(1,3-benzodioxol-5-yl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[4-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[3-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,1,3-benzothiadiazol-5-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[2-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-{[6-(4-methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-chloro-4-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-difluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(4-bromo-2-chloro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chloro-4-cyclopropyl-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chlorophenyl)methyl]-7-hydroxy-3,3-dimethyl-1,4-dihydropyrido[1,2-a]pyrazin-8-one-   2-[(2,4-dichloro-5-nitro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[1-(2-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(4-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2,5-dichlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-{1-[4-(trifluoromethyl)phenyl]ethyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[1-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(3-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-chloro-2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2,6-dimethoxyphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[1-(2,3,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-{1-[2-(benzyloxy)phenyl]ethyl}-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylpentyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-phenyl-3,4-dihydro-2H-chromen-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(3-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[cyclopentyl(phenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[1-(3-methoxyphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(3-chloro-2,6-difluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2,5-dimethylphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(1,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylbutyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   4-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]benzonitrile-   3-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]benzonitrile-   N-{3-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]phenyl}acetamide-   2-[1-(2,5-difluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(4-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-hydroxy-1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2,2,2-trifluoro-1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(1-phenylcyclopropyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-(2-fluoro-1-phenyl-ethyl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-(2,2-difluoro-1-phenyl-ethyl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-(1,3-benzothiazol-2-yl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(2-phenylcyclopropyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(5-quinolyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(3-phenyloxetan-3-yl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-(3-methylphenyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-2-[2-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   1,2-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-benzyl-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dichlorobenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   (1R)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   (1S)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dimethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   1-(4-fluorophenyl)-7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-(4-ethylbenzyl)-7-hydroxy-1-[3-(pyridin-3-yl)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-benzyl-7-hydroxy-3-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2,3-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   3-benzyl-2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   7-hydroxy-3-methyl-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-benzyl-7-hydroxy-3-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   2-benzyl-7-hydroxy-3-(2-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   9-chloro-2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   6-fluoro-7-hydroxy-2-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chlorophenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   9-chloro-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   9-chloro-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   9-bromo-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one-   9-bromo-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   2-[(2-chlorophenyl)methyl]-7-hydroxy-9-iodo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one-   9-cyclopropyl-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one    and-   2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one.

In some embodiments, the present invention provides prodrugs of thecompounds described herein. The term “prodrug” refers to an agent thatis converted into a biologically active form in vivo. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent compound. They may, for instance, be bioavailable byoral administration whereas the parent compound is not. The prodrug mayalso have improved solubility in pharmaceutical compositions over theparent drug. A prodrug may be converted into the parent drug by variousmechanisms, including enzymatic processes and metabolic hydrolysis.Typical examples of prodrugs include compounds that have biologicallylabile protecting groups on a functional moiety of the active compound.Prodrugs include compounds that can be oxidized, reduced, aminated,deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed,alkylated, dealkylated, acylated, deacylated, phosphorylated ordephosphorylated to produce the active compounds.

Prodrugs may be prepared by any variety of synthetic methods orappropriate adaptations presented in the chemical literature or as insynthetic or organic chemistry text books, such as those provide inGreen's Protective Groups in Organic Synthesis, Wiley, 4^(th) Edition(2007) Peter G. M. Wuts and Theodora W. Green; March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition(2007) Michael B. Smith and Domino Reactions in Organic Synthesis, Wiley(2006) Lutz F. Tietze, hereby incorporated by reference. Furtherinformation on the use of prodrugs may be found in Pro-drugs as NovelDelivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(Ed. E. B. Roche, American Pharmaceutical Association), also herebyincorporated by reference.

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compoundsdisclosed herein with certain moieties known to those skilled in the artas ‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some non-limiting examples of prodrugs in accordance with the inventioninclude: (i) where the exemplary compound contains a carboxylic acidfunctionality which is functionalized into a suitably metabolicallylabile group (esters, carbamates, etc.); (ii) where the exemplarycompound contains an alcohol functionality which is functionalized intoa suitably metabolically labile group (ethers, esters, carbamates,acetals, ketals, etc.); and (iii) where the exemplary compound containsa primary or secondary amino functionality, or an amide which arefunctionalized into a suitably metabolically labile group, e.g., ahydrolysable group (amides, carbamates, ureas, phosphonates, sulfonates,etc.). Further examples of replacement groups in accordance with theforegoing examples and examples of other prodrug types may be found inthe aforementioned references.

IV. Indications

As discussed above, the COMT-inhibiting compounds of the presentinvention can be used for treating neuropsychiatric and neurologicaldiseases for which inhibiting COMT provides a therapeutic benefit.

Significant psychiatric indications, as discussed above, include, butare not limited to ADHD, obsessive-compulsive disorder, alcoholism andother addictions, depression, bipolar disorder, age-associated cognitivesymptoms, impulse control disorders, including compulsive gambling,sexual behavior, and other compulsive destructive behaviors, inparticular, schizophrenia.

Among the preferred neurological diseases is treating Parkinson'sdisease, preferably when co-administered with L-DOPA, with or without anaromatic L-amino acid decarboxylase inhibitor (AADC) such as carbidopa,by preventing COMT-mediated metabolism of L-DOPA.

In one embodiment, a method for treating conditions in which inhibitionof COMT enzyme is beneficial comprises administering to a patient inneed thereof a COMT-inhibiting compound described hereinabove for use inthe present methods. Such conditions include, but are not limited to,those provided in WO 2011/109254, the contents of which are incorporatedherein by reference.

In a specific embodiment, a method for treating schizophrenia orpsychosis comprises administering to a patient in need thereof aCOMT-inhibiting compound described hereinabove for use in the presentmethods. The Diagnostic and Statistical Manual of Mental Disorders(DSM-IV-TR) (2000, American Psychiatric Association, Washington, D.C.)provides a diagnostic tool that includes paranoid, disorganized,catatonic or undifferentiated schizophrenia and substance-inducedpsychotic disorders. As used herein, the term “schizophrenia orpsychosis” includes the diagnosis and classification of these mentaldisorders as described in DSM-IV-TR and the term is intended to includesimilar disorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, conditions ordiseases such as schizophrenia or psychosis, including schizophrenia(paranoid, disorganized, catatonic, undifferentiated, or residual type),schizophreniform disorder, schizoaffective disorder, for example of thedelusional type or the depressive type, delusional disorder, psychoticdisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (for example psychosis induced by alcohol, amphetamine,cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine,ketamine and other dissociative anaesthetics, and otherpsychostimulants), psychosis/psychotic disorder, psychosis associatedwith affective disorders, brief reactive psychosis, schizoaffectivepsychosis, “schizophrenia-spectrum” disorders such as schizoid orschizotypal personality disorders, personality disorder of the paranoidtype, personality disorder of the schizoid type, illness associated withpsychosis (such as major depression, manic depressive (bipolar)disorder, Alzheimer's disease and post-traumatic stress syndrome),including both the positive and the negative symptoms of schizophreniaand other psychoses.

In another specific embodiment, a method for treating cognitivedisorders comprises administering to a patient in need thereof aCOMT-inhibiting compound described hereinabove for use in the presentmethods. The DSM-IV-TR also provides a diagnostic tool that includescognitive disorders including dementia, delirium, amnestic disorders andage-related cognitive decline. As used herein, the term “cognitivedisorders” includes the diagnosis and classification of these disordersas described in DSM-IV-TR and the term is intended to include similardisorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, disorders thatcomprise as a symptom a deficiency in attention and/or cognition, suchas dementia (associated with Alzheimer's disease, ischemia,multi-infarct dementia, trauma, intracranial tumors, cerebral trauma,vascular problems or stroke, alcoholic dementia or other drug-relateddementia, AIDS, HIV disease, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, othergeneral medical conditions or substance abuse), mild cognitiveimpairment, multi-infarct dementia, Lewy body dementia, AIDS-relateddementia, and frontotemporal dementia, delirium, amnestic disorders orage related cognitive decline.

In another specific embodiment, a method for treating anxiety disorderscomprises administering to a patient in need thereof a COMT-inhibitingcompound described hereinabove for use in the present methods. TheDSM-IV-TR also provides a diagnostic tool that includes anxietydisorders as generalized anxiety disorder, obsessive-compulsive disorderand panic attack. As used herein, the term “anxiety disorders” includesthe diagnosis and classification of these mental disorders as describedin DSM-IV-TR and the term is intended to include similar disordersdescribed in other sources. Disorders and conditions encompassed hereininclude, but are not limited to, anxiety disorders such as, acute stressdisorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition.

In another specific embodiment, a method for treating substance-relateddisorders and addictive behaviors comprises administering to a patientin need thereof a COMT-inhibiting compound described hereinabove for usein the present methods. The DSM-IV-TR also provides a diagnostic toolthat includes persisting dementia, persisting amnestic disorder,psychotic disorder or anxiety disorder induced by substance abuse, andtolerance of, dependence on or withdrawal from substances of abuse. Asused herein, the term “substance-related disorders and addictivebehaviors” includes the diagnosis and classification of these mentaldisorders as described in DSM-IV-TR and the term is intended to includesimilar disorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, substance-relateddisorders and addictive behaviors, such as substance-induced delirium,persisting dementia, persisting amnestic disorder, psychotic disorder oranxiety disorder, drug addiction, tolerance, and dependence orwithdrawal from substances including alcohol, amphetamines, cannabis,cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine,sedatives, hypnotics or anxiolytics.

In another specific embodiment, a method for treating obesity or eatingdisorders associated with excessive food intake, and complicationsassociated therewith, comprises administering to a patient in needthereof a COMT-inhibiting compound described hereinabove for use in thepresent methods. At present, obesity is included in the tenth edition ofthe International Classification of Diseases and Related Health Problems(ICD-10) (1992 World Health Organization) as a general medicalcondition. The DSM-IV-TR also provides a diagnostic tool that includesobesity in the presence of psychological factors affecting medicalcondition. As used herein, the term “obesity or eating disordersassociated with excessive food intake” includes the diagnosis andclassification of these medical conditions and disorders described inICD-10 and DSM-IV-TR and the term is intended to include similardisorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, obesity, bulimianervosa and compulsive eating disorders.

In another specific embodiment, a method for treating mood anddepressive disorders comprises administering to a patient in needthereof a COMT-inhibiting compound described hereinabove for use in thepresent methods. As used herein, the term “mood and depressivedisorders” includes the diagnosis and classification of these medicalconditions and disorders described in the DSM-IV-TR and the term isintended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, bipolar disorders, mood disorders including depressive disorders,major depressive episode of the mild, moderate or severe type, a manicor mixed mood episode, a hypomanic mood episode, a depressive episodewith atypical features, a depressive episode with melancholic features,a depressive episode with catatonic features, a mood episode withpostpartum onset, post-stroke depression; major depressive disorder,dysthymic disorder, minor depressive disorder, premenstrual dysphoricdisorder, post-psychotic depressive disorder of schizophrenia, a majordepressive disorder superimposed on a psychotic disorder such asdelusional disorder or schizophrenia, a bipolar disorder, for example,bipolar I disorder, bipolar II disorder, cyclothymic disorder,depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders.

In another specific embodiment, a method for treating pain comprisesadministering to a patient in need thereof a COMT-inhibiting compounddescribed hereinabove for use in the present methods. Particular painembodiments are bone and joint pain (osteoarthritis), repetitive motionpain, dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain and neuropathic pain.

In other specific embodiments, the COMT-inhibiting compounds describedhereinabove for use in the present methods can be used to treat othertypes of cognitive, learning and mental related disorders including, butnot limited to, learning disorders, such as a reading disorder, amathematics disorder, or a disorder of written expression,attention-deficit/hyperactivity disorder, age-related cognitive decline,pervasive developmental disorder including autistic disorder, attentiondisorders such as attention-deficit hyperactivity disorder (ADHD) andconduct disorder; an NMDA receptor-related disorder, such as autism,depression, benign forgetfulness, childhood learning disorders andclosed head injury; a neurodegenerative disorder or condition, such asneurodegeneration associated with traumatic brain injury, stroke,cerebral infarct, epileptic seizure, neurotoxin poisoning, orhypoglycemia-induced neurodegeneration; multi-system atrophy; movementdisorders, such as akinesias and akinetic-rigid syndromes (including,Parkinson's disease, drug-induced parkinsonism, post-encephaliticparkinsonism, progressive supranuclear palsy, multiple system atrophy,corticobasal degeneration, parkinsonism-ALS dementia complex and basalganglia calcification), medication-induced parkinsonism (such as,neuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Huntington's disease, dyskinesia associated with dopamineagonist therapy, Gilles de la Tourette's syndrome, epilepsy, muscularspasms and disorders associated with muscular spasticity or weaknessincluding tremors; dyskinesias, including tremor (such as, rest tremor,postural tremor, intention tremor and essential tremor), restless legsyndrome, chorea (such as Sydenham's chorea, Huntington's disease,benign hereditary chorea, neuroacanthocytosis, symptomatic chorea,drug-induced chorea and hemiballismus), myoclonus (including,generalised myoclonus and focal myoclonus), tics (including, simpletics, complex tics and symptomatic tics), dystonia (including,generalised, idiopathic, drug-induced, symptomatic, paroxysmal, andfocal (such as blepharospasm, oromandibular, spasmodic, spasmodictorticollis, axial dystonia, hemiplegic and dystonic writer's cramp));urinary incontinence; neuronal damage (including ocular damage,retinopathy or macular degeneration of the eye, tinnitus, hearingimpairment and loss, and brain edema); emesis; and sleep disorders,including insomnia and narcolepsy.

Of the disorders above, the treatment of schizophrenia, bipolardisorder, depression, including unipolar depression, seasonal depressionand post-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), learning disorders, pervasive developmentaldisorders, including autistic disorder, attention disorders includingAttention-Deficit Hyperactivity Disorder, autism, tic disordersincluding Tourette's disorder, anxiety disorders including phobia andpost-traumatic stress disorder, cognitive disorders associated withdementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease,spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment andloss are of particular importance.

In particularly desirable embodiments, the COMT-inhibiting compounds,including the compounds of the present invention, are useful fortreating Alzheimer's disease. Accordingly, a method for treatingAlzheimer's disease comprises administering to a patient in need thereofa COMT-inhibiting compound described hereinabove for the presentmethods.

In other particularly desirable embodiments, the COMT-inhibitingcompounds, including the compounds of the present invention, are usefulfor treating Parkinson's disease. Accordingly, a method for treatingParkinson's disease comprises administering to a patient in need thereofa COMT-inhibiting compound described hereinabove for the presentmethods.

In yet other particularly desirable embodiments, the COMT-inhibitingcompounds, including the compounds of the present invention, are usefulfor treating mild cognitive impairment. Accordingly, a method fortreating mild cognitive impairment comprises administering to a patientin need thereof a COMT-inhibiting compound described hereinabove for thepresent methods.

In still other particularly desirable embodiments, the COMT-inhibitingcompounds, including the compounds of the present invention, are usefulfor treating cognitive, learning and mental related disorders inpatients with neurodegeneration associated with traumatic brain injury.Accordingly, a method for treating cognitive, learning and mentalrelated disorders in patients with neurodegeneration associated withtraumatic brain injury comprises administering a COMT-inhibitingcompound described hereinabove for the present methods.

In further particularly desirable embodiments, the COMT-inhibitingcompounds, including the compounds of the present invention, are usefulfor treating schizophrenia. Accordingly, a method for treatingschizophrenia comprises administering to a patient in need thereof aCOMT-inhibiting compound described hereinabove for the present methods.

The subject COMT-inhibiting compounds, including the compounds of thepresent invention, are useful in methods for the prevention, treatment,control, amelioration, or reduction of risk of the diseases, disordersand conditions noted herein.

V. Combination Therapies

The subject COMT-inhibiting compounds, including the compounds of thepresent invention, are further useful in a method for the prevention ortreatment of the aforementioned diseases, disorders and conditions incombination with other agents. In many instances, the combination of thedrugs together is safer or more effective than either drug alone; thecompounds of the present invention and the other active ingredients mayoften be used in lower doses than when each is used singly. The drug(s)in the combination may be administered contemporaneously or sequentially(i.e. one preceding or following the other, at any appropriate timeinterval). When administered contemporaneously, the drugs may beadministered separately, or a single dosage form may contain both activeagents.

Accordingly, the subject compounds may be used in combination with otheragents which are known to be beneficial in the subject indications, orother drugs that affect receptors or enzymes that either increase theefficacy, safety, convenience, or reduce unwanted side effects ortoxicity of the compounds of the present invention. It will beappreciated that any of the drugs listed herein may be in the form of apharmaceutically acceptable salt.

In a particularly preferred embodiment, the subject compound is employedin combination with levodopa, with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide. In otherembodiments, the COMT inhibitor of the invention is administered incombination with anticholinergics such as biperiden and trihexyphenidyl(benzhexol) hydrochloride, other COMT inhibitors such as entacapone,MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists,cholinergic agonists, NMDA receptor antagonists, serotonin receptorantagonists and dopamine receptor agonists such as alentemol,bromocriptine, fenoldopam, lisuride, naxagolide, pergolide andpramipexole.

In another embodiment, the subject compound may be employed incombination with a neuroleptic or antipsychotic agent, orpharmaceutically acceptable salts thereof. Classes of neuroleptic agentsinclude phenothiazines; thioxanthenes; heterocyclic dibenzazepines;butyrophenones; diphenylbutylpiperidines; indolones, such asacepromazine, amisulpride, amoxapine, aripiprazole, asenapine,benperidol, bifeprunox, blonanserin, brexpiprazole, bromperidol,bupropion, busprione, capuride, cariprazine, carpipramine,chlorpromazine, chlorprothixene, clocapramine, clopenthixol,cloperidone, clotiapine, clozapine, cyamemazine, dexclamol, divalproex,dixyrazine, droperidol, flupentixol tiotixene, flupentixol,fluphenazine, fluphenazine, fluspirilene, haloperidol, hydroxyzine,iloperidone, levomepromazine, loxapine, lurasidone, melperone,mesoridazine, molindone, moperone, mosapramine, nefazodone, nemonapride,olanzapine, paliperidone, penfluridol, perazine, pericyazine, perlapine,perospirone, perphenazine, perphenazine, phenelzine, pimavanserin,pimozide, pipamperone, pipotiazine, prochlorperazine, promazine,promethazine, prothipendyl, quetiapine, remoxipride, risperidone,roletamide, sertindole, sulpiride, sultopride, thioproperazine,thioridazine, thiothixene, timiperone, tranylcypromaine, trazodone,trepipam, trifluoperazine, triflupromazine, trimipramine, veralipride,zicronapine, ziprasidone, zotepine, or zuclopenthixol.

In one embodiment, the subject compound may be employed in combinationwith anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen,vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antianxiety agents,cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minortranquilizers, melatonin agonists and antagonists, melatonergic agents,benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as:adinazolam, allobarbital, alonimid, alprazolam, amitriptyline,amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam,butabarbital, butalbital, capuride, carbocloral, chloral betaine,chloral hydrate, clonazepam, clorazepate, chlordiazepoxide, clorethate,cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone,divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol,etomidate, fenobam, flupentixol, fiurazepam, fluvoxamine, fluoxetine,fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium,lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin,mephobarbital, meprobamate, methaqualone, midaflur, midazolam,nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde,paroxetine, pentobarbital, perlapine, phenelzine, phenobarbital,prazepam, propofol, protriptyline, quazepam, reclazepam, roletamide,secobarbital, sertraline, suproclone, temazepam, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,zolazepam, or zolpidem.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,β-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT1A agonists orantagonists, especially 5-HT1A partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid,phenelzine, tranylcypromine and selegiline; moclobemide; venlafaxine;duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone andviloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

VI. Formulation and Administration

The invention provides a method for administering a COMT inhibitingcompound as provided herein to a patient suffering from a condition, orprone to a condition, that is responsive to treatment or prevention withthe compound. The method comprises administering, e.g. orally orparenterally, a therapeutically effective amount of the compound,preferably provided as part of a pharmaceutical preparation.

In some embodiments, a prodrug of the COMT inhibiting compound isadministered.

The invention also provides pharmaceutical preparations comprising aCOMT-inhibiting compound as provided herein in combination with apharmaceutical excipient.

Modes of administration include administration by injection, e.g.parenteral, intravenous, intraarterial, intramuscular, subcutaneous, andintrathecal, as well as pulmonary, rectal, transdermal, transmucosal,and oral delivery.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, or other bovine, ovine, equine, canine,feline, or rodent, such as mouse, species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

Suitable formulation types for parenteral administration includeready-for-injection solutions, dry powders for combination with asolvent prior to use, suspensions ready for injection, dry insolublecompositions for combination with a vehicle prior to use, emulsions andliquid concentrates for dilution prior to administration.

The pharmaceutical carrier(s) employed may be solid or liquid. Liquidcarriers can be used in the preparation of solutions, emulsions,suspensions and pressurized compositions. The compounds are dissolved orsuspended in a pharmaceutically acceptable liquid excipient. Suitableexamples of liquid carriers for parenteral administration include, butare not limited to, water (which may contain additives, e.g., cellulosederivatives, preferably sodium carboxymethyl cellulose solution),phosphate buffered saline solution (PBS), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) and their derivatives,and oils (e.g., fractionated coconut oil and arachis oil). The liquidcarrier can contain other suitable pharmaceutical additives including,but not limited to, the following: solubilizers, suspending agents,emulsifiers, buffers, thickening agents, colors, viscosity regulators,preservatives, stabilizers and osmolarity regulators.

Exemplary excipients include, without limitation, carbohydrates,inorganic salts, antimicrobial agents, antioxidants, surfactants,buffers, acids, bases, and combinations thereof. A carbohydrate such asa sugar, a derivatized sugar such as an alditol, aldonic acid, anesterified sugar, and/or a sugar polymer may be present as an excipient.Specific carbohydrate excipients include, for example: monosaccharides,such as fructose, maltose, galactose, glucose, D-mannose, sorbose, andthe like; disaccharides, such as lactose, sucrose, trehalose,cellobiose, and the like; polysaccharides, such as raffinose,melezitose, maltodextrins, dextrans, starches, and the like; andalditols, such as mannitol, xylitol, maltitol, lactitol, xylitol,sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

The excipient can also include an inorganic salt or buffer including,but not limited to, citric acid, sodium chloride, potassium chloride,sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodiumphosphate dibasic, and combinations thereof.

A surfactant may be present as an excipient. Exemplary surfactantsinclude, but are not limited to, polysorbates such as Tween 20 and Tween80 and pluronics such as F68 and F88 (both available from BASF, MountOlive, N.J.); sorbitan esters; lipids, such as phospholipids such aslecithin and other phosphatidyl cholines, phosphatidyl ethanolamines(although preferably not in liposomal form), and fatty acids and fattyesters.

Acids or bases may be present as an excipient in the preparation.Nonlimiting examples of acids that can be used include those acidsselected from the group consisting of hydrochloric acid, acetic acid,phosphoric acid, citric acid, malic acid, lactic acid, formic acid,trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid,sulfuric acid, fumaric acid, and combinations thereof. Examples ofsuitable bases include, without limitation, bases selected from thegroup consisting of sodium hydroxide, sodium acetate, ammoniumhydroxide, potassium hydroxide, ammonium acetate, potassium acetate,sodium phosphate, potassium phosphate, sodium citrate, sodium formate,sodium sulfate, potassium sulfate, potassium fumarate, and combinationsthereof.

For parenteral administration, the carrier can also be an oily estersuch as ethyl oleate and isopropyl myristate. Sterile carriers areuseful in sterile liquid form compositions for parenteraladministration. Sterile liquid pharmaceutical compositions, solutions orsuspensions can be utilized by, for example, intraperitoneal injection,subcutaneous injection, intravenously, or topically. The compositionscan also be administered intravascularly or via a vascular stent.

For pressurized compositions, the liquid carrier can be a halogenatedhydrocarbon or other pharmaceutically acceptable propellant. Suchpressurized compositions may also be lipid encapsulated for delivery viainhalation. For administration by intranasal or intrabronchialinhalation or insufflation, the compositions may be formulated into anaqueous or partially aqueous solution, which can then be utilized in theform of an aerosol.

The compositions may be administered topically, as a solution, cream, orlotion, by formulation with pharmaceutically acceptable vehiclescontaining the active compound. The compositions can be in a formsuitable for use in transdermal devices.

The compositions of this invention may be orally administered, informulations such as capsules, tablets, powders or granules, or assuspensions or solutions in water or non-aqueous media. In the case oftablets for oral use, carriers that are commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried corn starch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

The amount of the compound in the composition will vary depending on anumber of factors, but will optimally be a therapeutically effectivedose when the composition is stored in a unit dose container (e.g., avial). In addition, the pharmaceutical preparation can be housed in asyringe. A therapeutically effective dose can be determinedexperimentally by repeated administration of increasing amounts of theCOMT-inhibiting compound in order to determine which amount produces aclinically desired endpoint.

The amount of any individual excipient in the composition will varydepending on the activity of the excipient and particular needs of thecomposition. Typically, the optimal amount of any individual excipientis determined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters, and thenfurther exploring the range at which optimal performance is attainedwith no significant adverse effects. Generally, however, the excipientwill be present in the composition in an amount of about 1% to about 99%by weight, preferably from about 5%-98% by weight, more preferably fromabout 15-95% by weight of the excipient, with concentrations less than30% by weight most preferred.

The foregoing pharmaceutical excipients, along with other excipients,are described in “Remington: The Science & Practice of Pharmacy”, 21sted., Williams & Williams, (2005), the “Physician's Desk Reference”, 67thed., PDR Network, Montvale, N.J. (2013), and Kibbe, A. H., “Handbook ofPharmaceutical Excipients”, 7th Edition, Pharmaceutical Press,Washington, D.C., 2012.

The dose of the compounds according to the invention to be administered,both unit dosage and dosing schedule, will vary depend upon the age,weight, and general condition of the subject, as well as the desiredtherapeutic effect, the route of administration, and the duration of thetreatment. The compounds of the invention are administered to thepatient in therapeutically effective amounts. Methods are known to thoseskilled in the art to adjust the dose to obtain maximal benefit.Generally, dosage levels of between 0.001 to 10 mg/kg of body weightdaily are administered to the patient. The dosage range will generallybe about 0.5 mg to 1.0 g per patient per day, which may be administeredin single or multiple doses. In one embodiment, the dosage range will beabout 0.5 mg to 500 mg per patient per day; in another embodiment about0.5 mg to 200 mg per patient per day; and in yet another embodimentabout 5 mg to 50 mg per patient per day. The compounds may beadministered on a regimen of 1 to 4 times per day, such as once or twiceper day.

These and other aspects of the invention will be realized upon closerinspection of the specification as a whole.

EXAMPLES

The present compounds can be prepared and evaluated according toprocedures provided in the following Examples. The following Examplesfurther describe, but do not limit, the scope of the invention.

COMT Inhibition Assay Procedure

The ability of compounds to inhibit the activity ofcatechol-O-methyltransferase (COMT) was determined by a homogenoustime-resolved fluorescent (HTRF) assay (Lina et al, 2012; kit fromCisBio, Codolet, France). This assay measures the production ofS-adenosyl homocysteine (SAH) from the methyl donor S-adenosylmethionine. Recombinant human membrane bound COMT (MB-COMT; M51Avariant) was expressed in HEK 293F cells using 293Fectin (LifeTechnologies, Gent, Belgium) and membranes prepared. The membranes werere-suspended in buffer (20 mM Tris/HCl pH 7; 10 mM glycerol; 2 mM MgCl₂;10 mM NaCl), aliquoted and stored at −80° C.

Recombinant human soluble COMT(S-COMT), Val58 variant and a hexa-His tagon the N-terminus, was purified using Ni-NTA chromatography, the His tagremoved and stored in buffer as above.

For the human MB-COMT assay, membranes (62 ng/well) were incubated withSAM (20 μM final, CisBio) and dopamine (1.5 μM final; Sigma H8502,Diegem, Belgium) in the presence or absence of varying concentrations(typically 10 concentrations ranging from 10

M to 0.1 nM) of compound for 40 min at 37° C. in 384-well microtiterplates (10

l per well final volume). The reaction was terminated by the addition ofacylation buffer and the amount of SAH produced determined according tomanufacturer's instructions. Specific inhibition as that inhibited by ahigh concentration of tolcapone and all experiments were validated usinga control curve to tolcapone.

The human S-COMT assay was performed as above except that 0.15 ngenzyme/well was incubated with SAM (20 μM final) and dopamine (100 μMfinal) for 15 min at 37° C. and SAH production determined.

HTRF readings were performed using a Perkin Elmer Envision and resultsexpressed as concentration of SAH produced using a standard curve.Results were analyzed using non-linear regression to the 4-parameterlogistic equation and pIC50 (−log 10 concentration of drug whichinhibits enzyme activity/SAH production by 50%) determined.

As the data herein indicate, a broad variety of compounds of formula Iwere found effective as COMT inhibitors at low concentrations. pIC₅₀values for exemplary compounds of formula I (see below for compoundnames and structures) are provided in Table 1 below. Any compound with apIC₅₀ superior or equal to 4.5 in this assay, as described above, isdeemed a COMT inhibitor. In the Table 1 below, a single plus (+) isassociated with a pIC₅₀ of from about 4.5 to 6; two plus signs (++) isassociated with a pIC₅₀ of from about 6 to 7; and three plus signs (+++)is associated with a pIC₅₀ of above about 7.

TABLE 1 Example Activity range 1 ++ 2 ++ 3 + 4 + 5 + 6 +++ 7 +++ 8 +++ 9+++ 10 +++ 11 ++ 12 ++ 13 +++ 14 +++ 15 ++ 16 +++ 17 ++ 18 +++ 19 ++ 20++ 21 +++ 22 ++ 23 +++ 24 +++ 25 +++ 26 ++ 27 +++ 28 +++ 29 +++ 30 ++ 31++ 32 ++ 33 +++ 34 ++ 35 ++ 36 +++ 37 +++ 38 ++ 39 +++ 40 ++ 41 ++ 42 ++43 ++ 44 +++ 45 ++ 46 ++ 47 +++ 48 ++ 49 ++ 50 ++ 51 ++ 52 +++ 53 +++ 54++ 55 ++ 56 ++ 57 +++ 58 +++ 59 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64 +++65 ++ 66 +++ 67 +++ 68 ++ 69 +++ 70 ++ 71 ++ 72 ++ 73 +++ 74 ++ 75 +++76 +++ 77 +++ 78 +++ 79 +++ 80 ++ 81 ++ 82 +++ 83 ++ 84 ++ 85 +++ 86 +++87 +++ 88 +++ 89 ++ 90 +++ 91 +++ 92 +++ 93 ++ 94 ++ 95 ++ 96 ++ 97 +++98 ++ 99 ++ 100 + 101 +++ 102 ++ 103 ++ 104 +++ 105 +++ 106 +++ 107 +++108 ++ 109 ++ 110 + 111 ++ 112 +++ 113 ++ 114 ++ 115 ++ 116 +++ 117 +++118 +++ 119 +++ 120 +++ 121 +++ 122 +++ 123 +++ 124 +++ 125 +++ 126 +++127 +++ 128 ++ 129 ++ 130 ++ 131 ++ 132 +++ 133 +++ 134 ++ 135 ++ 136+++ 137 +++ 138 +++ 139 +++ 140 + 141 ++ 142 +++

Synthetic Procedures

Exemplary compounds were prepared via several general synthetic routesset forth in the Examples below. Any of the disclosed compounds of thepresent invention can be prepared according to one or more of thesesynthetic routes or specific examples, or via modifications thereofaccessible to the person of ordinary skill in the art.

Intermediate 1: 7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step1: Preparation of1-(2-aminoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

Ethylenediamine (45.3 g, 754 mmol, 50.9 mL) was added to a suspension of5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (35 g, 151 mmol) inethanol (350 mL). The mixture was heated at 90° C. for 1.5 h. Thereaction mixture was concentrated to yield the title intermediate as abrown viscous oil (46.4 g, quant.) used as such in the next experimentwithout further purification. MS, ES⁺ m/z 275.2 [M+H]⁺.

Method A Step 2a: Preparation of7-benzyloxy-3,4-dihydropyrido[1,2-a]pyrazin-8-one

1-(2-aminoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one (49 g, 179mmol) was dissolved in CHCl₃ (400 mL) and MnO₂ (78 g, 893 mmol) wasadded to the mixture and heated overnight at 60° C. The reaction mixturewas filtered and the residue was concentrated to yield the titleintermediate used in the next step without further purification. MS, ES⁺m/z 255.5 [M+H]⁺.

Step 2b: Preparation of7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

7-benzyloxy-3,4-dihydropyrido[1,2-a]pyrazin-8-one (46.4 g, 182 mmol) wasdissolved in MeOH (500 mL). NaBH4 (20.71 g, 547 mmol) was addedportionwise to the mixture and the mixture was stirred over 48 h at rt.The reaction mixture was then concentrated to give a residue (10 g) thatwas purified by chromatography (SiO₂, DCM:MeOH:NH₃ (7 N) (90:9:1) toyield the title intermediate as a yellow solid (23.4 g, 50%). MS, ES⁺m/z 257.2 [M+H]⁺.

¹H-NMR (300 MHz, DMSO-d₆)

7.45-7.22 (m, 6H), 5.90 (s, 1H), 4.96 (s, 2H), 3.74 (t, J=5.6 Hz, 2H),3.70 (br. s., 2H), 3.00 (t, J=5.6 Hz, 2H), 2.57 (br. s., 1H), 1H-NMR(300 MHz, MeOD)

7.48-7.42 (m, 3H), 7.38-7.26 (m, 3H), 6.25 (s, 1H), 5.06 (s, 1H),3.97-3.81 (m, 4H), 3.28 (t, J=5.6 Hz, 2H).

Intermediate 2:7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)-4Hpyran-4-one

To a suspension of Kojic acid (25.4 g, 179 mmol) in anhydrous DMF (450mL) was added potassium carbonate (29.6 g, 214 mmol) andalpha-chloro-4-methoxytoluene (30.8 g, 197 mmol, 26.7 mL) and theresulting suspension was stirred at 80° C. for 4 h. The reaction mixturewas evaporated in vacuo (oil pump, high vacuum) and water (500 mL) wasadded. The resulting suspension was stirred for 30 minutes. The solidswere filtered off and dried under air current for 30 minutes, thentriturated from heptane:diethyl ether (1:1, 300 mL) and dried in avacuum oven (40° C.) overnight to yield 38.44 g of the titleintermediate as a brown solid used in the next step without any furtherpurification.

Step 2: Preparation of1-(2-aminoethyl)-2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)pyridin-4(1H)-one

Ethylenediamine (38.2 g, 635 mmol, 42.9 mL) was added to a suspension of2-hydroxymethyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (33.3 g, 127mmol) in Ethanol (400 mL). The reaction mixture was stirred for 4 h at90° C. and then stirred overnight at rt. The reaction mixture wasconcentrated to yield the title intermediate (50.3 g) as a brown viscousoil used in the next step without any further purification. MS, ES⁺ m/z305.2 [M+H]⁺.

Step 3: Preparation of7-((4-methoxybenzyl)oxy)-3H-pyrido[1,2-a]pyrazin-8(4H)-one

1-(2-aminoethyl)-2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)pyridin-4(1H)-one(38.6 g, 127 mmol) was dissolved in chloroform (400 mL) and stirred fora few minutes. MnO₂ (55.1 g, 634 mmol) was added to the mixture wasstirred at 60° C. overnight. The reaction mixture was filtered and theresidue was concentrated to yield the title intermediate (47.5 g). MS,ES⁺ m/z 285.2 [M+H]⁺.

Step 4: Preparation of7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

To a cooled (ice bath) solution of7-[(4-methoxyphenyl)methoxy]-3,4-dihydropyrido[1,2-a]pyrazin-8-one (5.0g, 17.59 mmol) in MeOH (100 mL) was added NaBH₄ (672 mg, 1 eq.) and theresulting mixture was stirred at rt for 14 h. The reaction mixture wasfiltered on a bed of celite/silicagel/celite and rinsed with MeOH (3×10mL). The solvent was evaporated to give a pale yellow solid (6.1 g).This solid was then dissolved in a DCM/MeOH (9:1). The mixture was thenwashed with an aq. saturated solution of NaCl. The organic layers weredried on MgSO₄ and concentrated under vacuum to yield the titleintermediate as a yellow solid (4.6 g, 90%). MS, ES⁺ m/z 287.2 [M+H]⁺.¹H-NMR (300 MHz, DMSO-d₆)

7.35 (s, 1H), 7.31 (d, J=4.3 Hz, 2H), 6.91 (d, J=4.3 Hz, 2H), 5.88 (s,1H), 4.89 (s 2H), 3.75-3.71 (m, 4H), 3.73 (s, 3H), 3.01 (t, J=5.9, 2H),1H-NMR (300 MHz, MeOD) O 7.42 (s, 1H), 7.36 (d, J=4.3 Hz, 2H), 6.90 (d,J=4.3 Hz, 2H), 6.25 (s, 1H), 5.05 (s 2H), 3.97-3.92 (m, 4H), 3.78 (s,3H), 3.19 (t, J=5.9, 2H).

Intermediate 3:5-benzyloxy-1-(2-chloroethyl)-2-(chloromethyl)pyridin-4-one

Step 1: Preparation of5-benzyloxy-1-(2-hydroxyethyl)-2-(hydroxymethyl)pyridin-4-one

To a suspension of 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (9.90 g,42.7 mmol) in EtOH (20 mL) was added ethanolamine (3.0 mL, 49.2 mmol).The resulting mixture was stirred at reflux (bath oil heated at 110° C.)for 4.5 h and then at room temperature overnight. Ethanolamine (0.5 mL)was added and the mixture was stirred at reflux for another 1 h. Themixture was cooled to rt, then filtered. The collected solid was washedwith Et₂O (3×15 mL) to yield the title intermediate as a beige solid(9.7 g, 83%). This intermediate is used in the next step without furtherpurification. MS, ES⁺ m/z 275 [M+H]⁺.

Step 2: Preparation of5-benzyloxy-1-(2-chloroethyl)-2-(chloromethyl)pyridin-4-one Method B

A mixture of5-benzyloxy-1-(2-hydroxyethyl)-2-(hydroxymethyl)pyridin-4-one (980 mg,3.56 mmol) in CHCl₃ (6 mL) with SOCl₂ (2 mL) was stirred at 50° C. for 2h. Evaporation of the solvents under vacuum (40° C. overnight) gave 1.1g of a beige brown solid (quant.). MS, ES⁺ m/z 312 (M+H)⁺. Thisintermediate is used in the next step without further purification.

Intermediate 4: 5-benzyloxy-4-oxo-pyran-2-carbaldehyde

MnO₂ (18.7 g, 216 mmol) was added to a suspension of5-benzyloxy-2-(hydroxymethyl)pyran-4-one (43.1 mmol, 10 g) in toluene(150 mL). The mixture was heated at 100° C. for 14 h. The mixture wascooled to rt, filtered on a bed of celite then concentrated to yield thetitle intermediate as a colorless oil (6.0 g, 60%). This intermediate isused in the next step without further purification

Intermediate 5:N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]methylene]-2-methyl-propane-2-sulfinamide

Step 1: Preparation of5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(hydroxymethyl)pyridin-4-one

5-benzyloxy-2-(hydroxymethyl)pyran-4-one (55.2 g, 238 mmol) wassuspended in water (180 ml). 2-[tert-butyl(dimethyl)silyl]oxyethanamine(50 g, 285 mmol) and an aq. solution of NaOH (23.8 ml, 23.8 mmol, 1N)was added and the mixture was stirred at 60° C. for 2 h, then anadditional amount of 2-[tert-butyl(dimethyl)silyl]oxyethanamine (50 g,285 mmol) was added and the mixture was stirred at 60° C. for 14 h.Water was added, the mixture decanted and iPrOH (100 mL) was added.Ether was added (100 mL), until a beige precipitate was formed. Theprecipitate was filtered off, washed with ether and dried. The motherliquor was concentrated and ether was added. The precipitate wasfiltered off, washed with ether and combined with the first batch toafford the title intermediate as an off-white solid (43.5 g). MS, ES⁺m/z, 390.2 (M+H)⁺.

Step 2: Preparation of5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-pyridine-2-carbaldehyde

5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(hydroxymethyl)pyridin-4-one(43.8 g, 112 mmol) was dissolved in DCM (700 ml). Dess-Martinperiodinane (52.5 g, 124 mmol) was added and the mixture was stirred atrt for 2 h. The mixture was washed with an aq. sat. solution of sodiumbicarbonate (2×). The organic layer was dried with sodium sulfate andconcentrated to afford a yellow solid (56.5 g). Purification bychromatography (SiO₂, gradient up to 5% MeOH in DCM) gave the titleintermediate as a yellow oil (51 g). MS, ES⁺ m/z, 388.2 (M+H)⁺.

Step 3: Preparation ofN-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]methylene]-2-methyl-propane-2-sulfinamide

5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(hydroxymethyl)pyridin-4-one(51 g, 132 mmol) and 2-methylpropane-2-sulfinamide (19.14 g, 158 mmol)were dissolved in DCM (1 L). Titanium (IV) isopropoxide (46.3 mL, 158mmol) was added and the mixture was stirred overnight. The reactionmixture was concentrated (87 g crude) and filtered over a plug of silica(10% MeOH in DCM) to afford the title intermediate as a yellow solid/oil(65.95 g, 95%). MS, ES⁺ m/z, 491.2 (M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆)

8.51 (s, 1H), 7.75 (s, 1H), 7.44-7.27 (m, 5H), 6.73 (s, 1H), 5.04 (s,2H), 4.44-4.23 (m, 2H), 3.91-3.71 (m, 2H), 1.18 (s, 9H), 0.73 (s, 9H),0.15 (s, 3H), 0.14 (s, 3H).

Intermediate 6:7-benzyloxy-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation ofN-[1-[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide

N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]methylene]-2-methyl-propane-2-sulfinamide(Intermediate 5, 20 g, 40.8 mmol) was dissolved in THF (dry) (500 mL),the mixture was cooled to −15° C. under a nitrogen atmosphere.Methylmagnesium bromide (1 N in THF, 122 mmol, 122 mL) was added and themixture was stirred 1 h and slowly warmed to 12° C. The mixture wasadded to aq. sat. solution of ammonium chloride, extracted with EtOAc.The combined organic layers were dried with Na₂SO₄ filtered andconcentrated under reduced pressure to give a white solid. Purificationby chromatography (SiO₂, 5-10% MeOH in DCM) yielded the titleintermediate (9.98 g, 48%). MS, ES⁺ m/z, 507.4 (M+H)⁺.

Step 2: Preparation ofN-[1-[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide

N-[1-[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide(9.98 g, 19.69 mmol) was dissolved in anhydrous DMF (100 mL). Cesiumfluoride (5.98 g, 39.4 mmol) was added to the stirred mixture andstirring was continued at room temperature for 20 h. The reactionmixture was added to a water/aq. sat. solution of NH₄Cl (1:1) andextracted with EtOAc. The organic phase was evaporated under vacuum. Theremaining aqueous phase were evaporated to dryness under reducedpressure (0.5 Torr) and stripped with toluene (100 mL), affording ayellow oil batch combined with the evaporated organic phase. Thismaterial was taken up in DCM:MeOH (1:1) and filtered over SiO₂ (elutingwith DCM:MeOH (1:1)) to yield the title intermediate (6.86 g, 89%). MS,ES⁺ m/z, 393.2 (M+H)⁺.

Step 3: Preparation of7-benzyloxy-2-tert-butylsulfinyl-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

A solution ofN-[1-[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide(6.68 g, 17.02 mmol) and triphenylphosphine (4.46 g, 17.02 mmol) inanhydrous THF (100 mL) was cooled to 0° C. The reaction mixture wasstirred and DIAD (4.16 g, 20.57 mmol, 4 mL) was added in 100 μLportions, until an orange color persisted. The reaction mixture wasstirred at room temperature over the weekend. The reaction mixture wasthen cooled to 0° C. and another portion of triphenylphosphine (4 g,15.25 mmol) and DIAD (4.16 g, 20.57 mmol, 4 ml) were added. Reactionmixture was stirred for 1 h while slowly warming to room temperature.The reaction mixture was evaporated to dryness to obtain a red oil (23.5g). Material was taken up in 50 mL MeOH and purified by automatedreversed phase chromatography (8 runs of 8 mL MeOH solution, 120 g C₁₈,water:CH3CN). The collected fractions were freeze-dried to yield thetitle intermediate (4.32 g, 68%). MS, ES⁺ m/z, 375.2 (M+H)⁺.

Step 4: Preparation of7-benzyloxy-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

A solution of7-benzyloxy-2-tert-butylsulfinyl-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(4.23 g, 11.30 mmol) in MeOH (50 mL) was cooled in an ice bath. Asolution of HCl (4 N in dioxane, 13.55 mmol, 3.39 mL) was added dropwiseand the stirring was continued for 15 min, while keeping the flask inthe ice bath. Diethyl ether (50 mL) was added to the reaction mixtureand the stirring continued for 30 minutes. The white precipitate wascollected by filtration. The filtrates were then evaporated to drynessand the residue was combined with the collected solid. The material wastaken up in MeOH:DCM (1:9, 50 mL). A solution of NH₃ in MeOH (7 N, 2.3mL) was added and hydromatrix (50 g) was added. The mixture wasevaporated to dryness under reduced pressure and charged on a SiO₂column (100 g silica, DCM:MeOH (95:5)) until molybdate staining revealedno side products anymore. Subsequently, the product was eluted withDCM:MeOH:NH₃/MeOH (8:2:0.1) to give the title intermediate (1.95 g,65%). MS, ES⁺ m/z, 271.2 (M+H)⁺. ¹H-NMR (300 MHz, MeOD)

7.46 (m, 3H), 7.38-7.24 (m, 3H), 6.62 (s, 1H), 5.09 (s, 2H), 4.12-3.95(m, 3H), 3.36-3.31 (m, 1H, coincides with solvent residual peak),3.23-3.14 (m, 1H), 1.49 (d, J=3.8 Hz).

Intermediate 7:7-benzyloxy-1-tetrahydropyran-4-yl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation ofN-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide

Under nitrogen atmosphere, magnesium (6.05 g, 249 mmol) was suspended inTHF (30 ml). A catalytic amount of iodine and dibromoethane (0.4 ml)were added. The mixture was heated to 60° C. and4-chlorotetrahydro-2H-pyran (5 g, 41.5 mmol) in THF (5 ml) was addeddropwise. The mixture was stirred at 60° C. for 2.5 h. The mixture wascooled to 0° C. andN-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]methylene]-2-methyl-propane-2-sulfinamide(Intermediate 5, 6.78 g, 13.82 mmol) in THF (20 ml) was added. Theresulting mixture was stirred at rt for 45 min. The reaction wasquenched with ammonium chloride solution and extracted with EtOAc (2×).The combined organic layers were washed with brine, dried with sodiumsulfate and concentrated to afford the title intermediate as an orangegum (8.7 g). Purification by chromatography (SiO₂, 10% MeOH in DCM) gavethe title intermediate as an orange oil (7.3 g, 56%). MS, ES⁺ m/z, 577(M+H)⁺.

Step 2: Preparation ofN-[[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide

N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide(7.3 g, 7.59 mmol) was dissolved in DMF (50 mL). Cesium fluoride (3.5 g,22.78 mmol) was added and the mixture was stirred at rt for 3 h.Additional Cesium fluoride (5 g) was added and the mixture was stirredover the weekend at rt. The mixture was concentrated and stripped withtoluene to afford a yellow oil (8.3 g). Purification by chromatography(SiO₂, 5% MeOH in DCM) afforded the title intermediate (2.12 g, 48%).MS, ES⁺ m/z, 463.2 (M+H)⁺.

Step 3: Preparation of7-benzyloxy-2-tert-butylsulfinyl-1-tetrahydropyran-4-yl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-[[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide(2.1 g, 3.63 mmol) and triphenylphosphine (1.1 g, 4.19 mmol) weredissolved in THF (30 mL). The mixture was cooled to 0° C. and DIAD (0.8ml, 4.11 mmol) was added until an orange color persisted. The mixturewas allowed to reach rt and stirred overnight. Additionaltriphenylphosphine (1.1 g, 4.19 mmol) and DIAD (0.8 mL, 4.11 mmol) wereadded and the mixture was stirred at rt for 2 h. The mixture wasconcentrated to afford an orange oil. Purification by chromatography(SiO₂, 5% MeOH in DCM) afforded an orange gum (1.95 g, 90%). MS, ES⁺m/z, 445.2 (M+H)⁺.

Step 4: Preparation of7-benzyloxy-1-tetrahydropyran-4-yl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

N-[[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide(1.95 g, 3.27 mmol) was dissolved in MeOH (4 mL). HCl (4 N in dioxane,1.2 ml, 4.9 mmol) was added and the mixture was stirred at rt for 30min. The mixture was concentrated, dissolved in MeOH (4 mL)/7N ammoniain MeOH (2 ml) and stirred for 15 min.

The resulting mixture was coated onto silica and purified with flashcolumn chromatography (7.5% MeOH in DCM) to afford the titleintermediate as a white foam (492 mg, 42%). MS, ES⁺ m/z, 341.2 (M+H)⁺.¹H-NMR (300 MHz, DMSO-d₆)

7.43-7.28 (m, 6H), 6.05 (s, 1H), 4.95 (s, 2H), 3.87-3.74 (m, 4H), 3.61(d, J=2.7 Hz, 1H), 3.29-3.19 (m, 1H, overlap with solvent residualpeak), 3.14-3.07 (m, 1H), 2.94-2.85 (m, 1H), 2.61 (bs, 1H), 2.04-1.90(m, 1H), 1.50 (qd, J1=6.2 Hz, J2=2.1 Hz, 1H), 1.41-1.28 (m, 3H),

Intermediate 8:7-benzyloxy-3-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of1-(2-amino-2-phenyl-ethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

Method C

1-phenyl-ethane-1,2-diamine (10.34 mmol, 1.482 g, 1.2 eq.) was added toa solution of 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (8.6 mmol, 2.0 g)in EtOH (15 mL) and the mixture was heated at 90° C. for 14 h.1-phenyl-ethane-1,2-diamine (0.2 g) was added and the mixture wasstirred for another 14 h. Water was added, then the mixture wasextracted with EtOAc. The combined organic layers were dried over MgSO4,filtered and concentrated to give a residue (3.4 g). Purification bychromatography (gradient from 3% methanolic ammonia in DCM up to 10%)gave the title intermediate (1.33 g, 45%). MS, ES⁺ m/z, 351.3 (M+H)⁺.

Step 2: Preparation of7-benzyloxy-3-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using1-(2-amino-2-phenyl-ethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one asa yellow oil. (77%). MS, ES⁺ m/z, 333.3 (M+H)⁺.

Intermediate 9:3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of1-(2-amino-3-phenyl-propyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

The title intermediate was prepared according to Method C using3-phenylpropane-1,2-diamine, and isolated as a brown oil (used in thenext step without purification). MS, ES⁺ m/z, 365.3 (M+H)⁺.

Step 2: Preparation of3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-oneinvolving a purification of the crude product by chromatography (SiO₂,7% methanolic ammonia in DCM) (45%). MS, ES⁺ m/z, 347.3 (M+H)⁺.

Intermediate 10:7-benzyloxy-3-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of1-(2-aminopropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

The title intermediate was prepared according to Method C using1,2-diaminopropane as a brown oil (56%). The crude product was purifiedby chromatography (SiO₂, DCM-MeOH—NH4OH 88-10.8-1.2). MS, ES⁺ m/z, 289.2(M+H)⁺.

Step 2: Preparation of7-benzyloxy-3-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using1-(2-aminopropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one as a yellowsolid (77%), used in the next step without any further purification.

Intermediate 11:7-benzyloxy-3,3-dimethyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of1-(2-amino-2-methylpropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

The title intermediate was prepared according to Method C using1,2-diamino-2-methylpropane. The crude product was purified bychromatography (SiO₂, 0-50% MeOH/DCM) to give1-(2-amino-2-methylpropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one asa tan gum (27%). MS, ES⁺ m/z, 303.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.53 (s, 1H) 7.30-7.42 (m, 5H) 6.23 (s,1H) 5.01 (s, 2H) 4.42 (s, 2H) 3.75 (s, 2H) 0.96 (s, 6H)

Step 2: Preparation of7-benzyloxy-3,3-dimethyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using1-(2-amino-2-methylpropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one.The crude product was purified by chromatography (SiO₂, 0-50% MeOH/DCM)to give7-benzyloxy-3,3-dimethyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one asa yellow solid (49%). MS, ES⁺ m/z, 285.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.30-7.44 (m, 6H) 5.98 (s, 1H) 4.97 (s,2H) 3.75 (s, 2H) 3.58 (s, 2H) 1.06 (s, 6H).

Example 1:2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-oneMethod D

7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate1, 55 mg, 0.22 mmol) was dissolved in EtOH (1 mL). Benzyl bromide (30μL, 0.25 mmol) and an aq. solution of NaOH (0.25 mL, 0.25 mmol, 1 N)were added. The mixture was stirred at 60° C. for 1 h. The reactionmixture was cooled to rt, then extracted with DCM (10 mL). The combinedorg. layers were washed with an aq. sat. solution of NaCl, dried overMgSO4, filtered and concentrated under vacuum. The residue was purifiedby column chromatography (SiO₂, gradient up to 10% methanolic ammonia inDCM) to yield the title intermediate as a light yellow oil (62 mg, 83%).MS, ES⁺ m/z, 347.4 (M+H)⁺.

Step 2: Preparation of2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-oneMethod E

2-benzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (99 mg,0.27 mmol) was dissolved in an aq. solution of HCl (7 mL, 5 N) andheated 1 h at 100° C. The mixture was cooled to rt, then washed withCHCl₃ (2×3 mL). The aq. phase was evaporated under vacuum to yield thetitle intermediate as a white solid (12 mg, 22%). High-Res MS, ES⁺ m/z,257.1276 (M+H)+(obs.), 257.129 (M+H)⁺ (calc.).

The following compound 2 has been synthesized according to Methods Dfollowed by Method E:

Preparation Example Name R Analytical data Information 2 7-hydroxy-2-[4-(trifluoromethyl) benzyl]-1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS ES⁺, 325.1144 (M + H)⁺ (obs.), 325.1164 (M + H)⁺ (calc.)Method D using 4- (trifluoromethyl)benzyl bromide, followed by Method E.3 2-[(4- fluorophenyl)methyl]- 7-hydroxy-3,4- dihydro-1H-pyrido[1,2-a]pyrazin- 8-one

MS, ES⁺ m/z, 275.2 (M + H)⁺. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (s, 1H) 7.44 (dd, J = 8.59, 5.81 Hz, 2 H) 7.17-7.27 (m, 2 H) 7.02 (s, 1 H)4.38 (t, J = 5.43 Hz, 2 H) 3.93 (s, 2 H) 3.83 (s, 2 H) 3.03 (t, J = 5.31Hz, 2 H) Method D using 4- fluoromethylbenzyl bromide, followed byMethod E. 4 2-[2-(benzotriazol-1- yl)ethyl]-7-hydroxy- 3,4-dihydro-1H-pyrido[1,2-a]pyrazin- 8-one

MS, ES⁺ m/z, 312.2 (M + H)⁺. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02- 8.08(m, 2 H) 7.97 (d, 1 H) 7.53-7.59 (m, 1 H) 7.38-7.44 (m, 1 H) 7.09 (s, 1H) 4.99 (t, 2 H) 4.30 (t, 2 H) 4.08 (br. s., 2 H) 3.20 (br. s., 2 H)3.14 (br. s., 2 H) Method D using 1-(2- bromoethyl)benzo- triazole,followed by Method E. 5 2-[2-(benzotriazol-2- yl)ethyl]-7-hydroxy-3,4-dihydro-1H- pyrido[1,2-a]pyrazin- 8-one

MS, ES⁺ m/z, 312.2 (M + H)⁺. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (s, 1H) 7.90-7.96 (m, 2 H) 7.42-7.47 (m, 2 H) 7.15 (s, 1 H) 5.06 (t, 2 H)4.35 (d, 2 H) 4.15 (br. s., 2 H) 3.41 (br. s., 2 H) 3.18 (br. s., 2 H)Method D using 2-(2- bromoethyl)benzo- triazole, followed by Method E.

Example 6:7-hydroxy-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-2-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneMethod F

7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate1, 150 mg, 0.59 mmol), 3-(trifluoromethoxy)benzaldehyde (130 μL, 0.86mmol), 4A molecular sieve (<5 μm, 72 mg), Si—BH₃CN (Silicycle, 1.81 g,1.6 mmol, 0.89 mmol/g) in EtOH (4 mL, 68.5 mmol) were dispersed in THF(2 mL). The mixture was stirred for 1 h at 40° C. before addition ofHOAc (0.5 mL, 9 mmol). The mixture was stirred again for an additional2.5 h at 40° C. Filtration on a bed of Celite (rinse with EtOAc, 3×20mL). The liquors were evaporated under vacuum to give a yellow oil (306mg). Purification by column chromatography (SiO₂, gradient 5% methanolicammonia in up to 10%) yielded the title intermediate as a white solid(87 mg, 35%). MS, ES⁺ m/z, 431.3 (M+H)⁺.

Step 2: Preparation of7-hydroxy-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared using7-benzyloxy-2-[[4-(trifuoromethyl)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-onefollowing to Method E, as a white solid (86%). High-Res MS, ES⁺,341.1116 (M+H)⁺ (obs.), 341.1113 (M+H)⁺ (calc.).

The following compounds 4-17 have been synthesized according to Method Ffollowed by Method E

Preparation Ex. Name R Analytical data Information 7 2-(4-tert-butylbenzyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 313.1917 (M + H)⁺ (obs.), 313.1916 (M + H)⁺ (calc.).Method F using 4- tert- butylbenzaldehyde, followed by Method E 87-hydroxy-2-[4- (trifluorometh- oxy)benzyl]- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 341.1118 (M + H)⁺ (obs.), 341.1113 (M + H)⁺ (calc.).Method F using 4- (trifluoromethyl) benzaldehyde, followed by Method E 92-(2,4- dimethylbenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS ES⁺, 285.1597 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.).Method F using 2,4- dimethylbenzaldehyde, followed by Method E 107-hydroxy-2-[4- (propan-2- yl)benzyl]- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS ES⁺, 299.1755 (M + H)⁺ (obs.), 299.1759 (M + H)⁺ (calc.).Method F using 4- isopropylbenzaldehyde, followed by Method E 117-hydroxy-2- (pyridin-2- ylmethyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 258.1242 (M + H)⁺ (obs.), 258.1242 (M + H)⁺ (calc.).Method F using pyridine-2- carbaldehyde, followed by Method E 127-hydroxy-2-[4- (pyridin-3- yl)benzyl]- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 334.1541 (M + H)⁺ (obs.), 334.1555 (M + H)⁺ (calc.).Method F using 4- (pyridine-3- yl)benzaldehyde, followed by Method E 132-(4- ethylbenzyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 285.1612 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.).Method F using 4- ethylbenzaldehyde, followed by Method E 147-hydroxy-2- (quinolin-8- ylmethyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 308.1383 (M + H)⁺ (obs.), 308.1399 (M + H)⁺ (calc.)Method F using Intermediate 2 and quinoline-8- carbaldehyde, followed byMethod E 15 7-hydroxy-2-(1- phenylethyl)- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 271.1434 (M + H)⁺ (obs.), 271.1447 (M + H)⁺ (calc.)Method F using acetophenone, purification by chromatography (SiO₂, 10%methanolic ammonia in DCM), followed by Method E 16 2-[1-(4-ethylphenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 299.1747 (M + H)⁺ (obs.), 299.1759 (M + H)⁺ (calc.).Method F using 4′- ethylacetophenone, purification by chromatography(SiO₂, 10% methanolic ammonia in DCM), followed by Method E

Example 17:2-[(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile

Step 1: Preparation of2-[[7-[(4-methoxyphenyl)methoxy]-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2-yl]methyl]benzonitrile

The title intermediate was prepared following to Method C starting fromintermediate 2 and 2-cyanobenzaldehyde (yield: 44%). MS, ES⁺, 402.1(M+H)⁺.

Step 2: Preparation of2-[(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile

TFA (0.4 mL) was added to a solution of2-[[7-[(4-methoxyphenyl)methoxy]-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2-yl]methyl]benzonitrile(185 mg, 0.46 mmol) in DCM (2 mL). The mixture was stirred at rt for 1h. Evaporation of the solvent under vacuum gave a residue that waspurified by reverse phase chromatography to yield the title compound asa beige solid (65 mg, 35%). MS, ES⁺, 282 (M+H)⁺.

Example 18:2-(4-ethyl-3-nitrobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

2-[(4-ethylphenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Example 13, 0.25 mmol, 70 mg) was poured in sulfuric acid (0.5 mL).Fuming nitric acid (0.26 mmol, 17 mg, 1.1 eq., 11 μL) was added and theresulting mixture stirred at rt for 10 min. Water (2 mL) was added andthe mixture was neutralized to pH 7 by the addition of an aq. solutionof K₂CO₃, then NaHCO₃. The precipitate was filtered, dried under vacuumto yield the title compound as an orange solid (38 mg, 47%). MS, ES⁺,330.29 (M+H)⁺.

Example 19:2-(2,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method G

0.6 mL of THF, 0.3 mL of EtOH and 0.1 mL of HOAc were added to7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate1, 19.2 mg, 0.075 mmol). 2,2-diphenylacetaldehyde (22 mg, 1.5 eq.)followed by Si—BH₃CN (Silicycle, 250 mg, 0.223 mmol, 3 eq.) were added.The resulting reaction mixture was stirred overnight at rt. The mixturewas filtered, evaporated. The residue was then dissolved in CH₃CN (2 mL)and purified by reverse phase preparative chromatography.

An aq. solution of HCl (1 mL, 6 N) was added to the purified andevaporated fractions and the mixture was heated at 100° C. for 1.5 h.The solvent was evaporated under vacuum. The residue was dissolved inCH₃CN/H₂O 75:25 (2 mL) and the solvents evaporated under vacuum to yieldthe title compound as a colorless film (28.4 mg). High-Res MS, ES⁺,347.1765 (M+H)⁺ (obs.), 347.1759 (M+H)⁺ (calc.).

The following compounds 21-52 have been synthesized according to MethodsG

Preparation Ex. Name R Analytical data Information 20 2-(2-ethylbutyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-

High-Res MS, ES⁺, 251.1755 (M + H)⁺ (obs.), 251.1759 (M + H)⁺ (calc.).Method G using 2- ethylbutyraldehyde a]pyrazin-8-one 21 2-(3,5-dichlorobenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 325.0521 (M + H)⁺ (obs.), 325.0511 (M + H)⁺ (calc.).Method G using 3,5- dichlorobenzalde- hyde 22 2- (cyclohexylmeth-yl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 263.1747 (M + H)⁺ (obs.), 263.1759 (M + H)⁺ (calc.).Method G using cyclohexane- carboxaldehyde 23 2-(4- cyclopropylben-zyl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 297.1603 (M + H)⁺ (obs.), 297.1603 (M + H)⁺ (calc.).Method G using 4- cyclopropyl- benzaldehyde 24 2-[(8,8- dimethyl-1,2,3,4,5,6,7,8- octahydronaph- thalen-2- yl)methyl]-7- hydroxy-

High-Res MS, ES⁺, 343.2372 (M + H)⁺ (obs.), 343.2386 (M + H)⁺ (calc.).Method G using 1,2,3,4,5,6,7,8- octahydro-8,8- dimethyl-2-naphthaldehyde 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one 252-(3,4- dichlorobenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 325.0516 (M + H)⁺ (obs.), 325.0511 (M + H)⁺ (calc.).Method G using 3,4- dichlorobenzalde- hyde 26 2- (cyclooctylmeth-yl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

LCMS (Method D, ES⁺) RT, (M + H)⁺, 98.8% purity. Method G usingcyclooctane- carbaldehyde 27 2-(2,6- dimethylbenzyl)- 7-hydroxy-1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 285.1591 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.)Method G using 2,6- dimethylbenzalde- hyde 28 2-(2,5- dimethylbenzyl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 285.1595 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.).Method G using 2,5- dimethylbenzalde- hyde 29 7-hydroxy-2- {[1-(phenylsulfonyl)- 1H-indol-2- yl]methyl}- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 436.1325 (M + H)⁺ (obs.), 436.1331 (M + H)⁺ (calc.).Method G using 1- (phenylsulfonyl)- 1h-indole-2- carbaldehyde 307-hydroxy-2-(3- phenylpropyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 285.1593 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.).Method G using 3- phenylpropional- dehdye 31 7-hydroxy-2-(2-phenylpropyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 285.1587 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.).Method G using 2- phenylpropional- dehyde 32 2-(3,5- difluorobenzyl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 293.1098 (M + H)⁺ (obs.), 293.1101 (M + H)⁺ (calc.).Method G using 2,6- difluorobenzalde- hyde 33 7-hydroxy-2-(2-methylbenzyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 271.1434 (M + H)⁺ (obs.), 271.1447 (M + H)⁺ (calc.).Method G using 2- methylbenzaldehyde 34 7-hydroxy-2- [(5-phenyl-1H-pyrazol-3- yl)methyl]- 1,2,3,4- tetrahydro-8H-

High-Res MS, ES⁺, 323.1483 (M + H)⁺ (obs.), 323.1508 (M + H)⁺ (calc.).Method G using 5-phenyl-1h- pyrazole-3- carbaldehyde pyrido[1,2-a]pyrazin-8-one 35 2-{[6-chloro-4- (1H-imidazol-4- yl)-3,4-dihydro-2H-chromen-8- yl]methyl}-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 413.1355 (M + H)⁺ (obs.), 413.138 (M + H)⁺ (calc.).Method G using 6-chloro-4-(1h- imidazol-4- yl)chromane-8- carbaldehyde36 7-hydroxy-2-(3- phenoxybenzyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 349.1562 (M + H)⁺ (obs.), 349.1552 (M + H)⁺ (calc.).Method G using 4- phenoxybenzalde- hyde 37 2-(2,3- dimethylbenzyl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 285.1581 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.).Method G using 2,3- dimethylbenzalde- hyde 38 2-(1,3- benzothiazol-2-ylmethyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺), 314.0943 (M + H)⁺ (obs.), 314.0963 (M + H)⁺ (calc.)Method G using 1,3- benzothiazole-2- carbaldehyde 39 2-(2-fluorobenzyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 275.1202 (M + H)⁺ (obs.), 275.1196 (M + H)⁺ (calc.)Method G using 2- fluorobenzaldehyde 40 2-[(5-chloro- 1,3-dimethyl-1H-pyrazol-4- yl)methyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-

High-Res MS, ES⁺, 309.1111 (M + H)⁺ (obs.), 309.1118 (M + H)⁺ (calc.).Method G using 5-chloro-1,3- dimethyl-1h- pyrazole-4- carbaldehydea]pyrazin-8-one 41 7-hydroxy-2- [(4-oxo-4H- chromen-3- yl)methyl]-1,2,3,4- tetrahydro-8H- pyrido[1,2-

High-Res MS, ES⁺, 325.1214 (M + H)⁺ (obs.), 325.1188 (M + H)⁺ (calc.).Method G using chromone-3- carboxaldehyde a]pyrazin-8-one 427-hydroxy-2- (1H-indazol-3- ylmethyl)- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 297.1372 (M + H)⁺ (obs.), 297.1351 (M + H)⁺ (calc.).Method G using 1h-indazole-3- carbaldehyde 43 7-hydroxy-2-{[3-(thiophen-2- yl)-1H-pyrazol- 4-yl]methyl}- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 329.1059 (M + H)⁺ (obs.), 329.1072 (M + H)⁺ (calc.).Method G using 3-(2-thienyl)-1h- pyrazole-4- carbaldehyde 447-hydroxy-2-[2- (trifluoromethyl) benzyl]- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 325.1154 (M + H)⁺ (obs.), 325.1164 (M + H)⁺ (calc.).Method G using 2- (trifluoromethyl) benzaldehyde 45 7-hydroxy-2-[(3-phenyl-1H- pyrazol-4- yl)methyl]- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 323.1494 (M + H)⁺ (obs.), 323.1508 (M + H)⁺ (calc.).Method G using 3-phenyl-1h- pyrazole-4- carbaldehyde 46 2-(2,6-dimethoxybenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 317.1486 (M + H)⁺ (obs.), 317.1501 (M + H)⁺ (calc.).Method G using 2,6- dimethoxybenzal- dehyde. 47 7-hydroxy-2-(4-phenoxybenzyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺), 349.1549 (M + H)⁺ (obs.), 349.1552 (M + H)⁺ (calc.).Method G using 4- phenoxybenzalde- hyde 48 2-(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 315.1329 (M + H)⁺ (obs.), 315.1345 (M + H)⁺ (calc.).Method G using 2,3-dihydro-1,4- benzodioxine-6- carbaldehyde 492-[3-(1,3- benzodioxol-5- yl)-2- methylpropyl]- 7-hydroxy- 1,2,3,4-tetrahydro-8H- pyrido[1,2-

High-Res MS, ES⁺, 343.1656 (M + H)⁺ (obs.), 343.1658 (M + H)⁺ (calc.).Method G using 3-(1,3- benzodioxol-5- yl)-2-methyl- propanala]pyrazin-8-one

Example 50:7-hydroxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method H

0.6 mL of THF, 0.3 mL of EtOH and 0.1 mL of HOAc were added to7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 2, 21.5 mg, 0.075 mmol). 4-methoxybenzaldehyde (22.1 mg,1.5 eq.) followed by MP-BH₃CN (SOPACHEM, 35 mg, 0.1851 mmol, 2.5 eq.)were added. The resulting reaction mixture was stirred overnight at rt.The mixture was filtered, evaporated. The residue was then dissolved inCH₃CN (2 mL) and purified by reverse phase preparative chromatography.DCM (0.5 mL) and TFA (0.5 mL) were added to the purified and evaporatedfractions and the mixture was stirred at rt for 2 h. The solvent wasevaporated under vacuum. The residue was dissolved in CH₃CN/H₂O 90:10 (2mL), filtered and the solvents evaporated under vacuum to yield thetitle compound as a colorless film (32.8 mg). High-Res MS, ES⁺287.1391(M+H)⁺ (obs.), 287.1396 (M+H)⁺ (calc.).

The following compounds 54-59 have been synthesized according to MethodH

Preparation Ex. Name R Analytical data Information 51 7-hydroxy-2-(2-methoxybenzyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 287.1399 (M + H)⁺ (obs.), 287.1396 (M + H)⁺ (calc.).Method H using 4- methoxybenzalde- hyde 52 2-[4- (benzyloxy)benzyl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 363.1693 (M + H)⁺ (obs.), 363.1709 (M + H)⁺ (calc.).Method H using 4- benzyloxybenzal- dehyde 53 2-[3- (benzyloxy)benzyl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺), 363.169 (M + H)⁺ (obs.), 363.1709 (M + H)⁺ (calc.).Method H using 3- benzyloxybenzal- dehyde 54 2-(2,1,3- benzothiadiazol-5-ylmethyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 315.09 (M + H)⁺ (obs.), 315.0916 (M + H)⁺ (calc.).Method H using 2,1,3- benzothiadiazole- 5-carbaldehyde 55 2-[2-(benzyloxy)benzyl]- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 363.1703 (M + H)⁺ (obs.), 363.1709 (M + H)⁺ (calc.).Method H using 2- benzyloxybenzal- dehyde 56 7-hydroxy-2- {[6-(4-methylphenyl)imi- dazo[2,1- b][1,3]thiazol-5- yl]methyl}- 1,2,3,4-tetrahydro-8H- pyrido[1,2-

High-Res MS, ES⁺, 393.137 (M + H)⁺ (obs.), 393.1385 (M + H)⁺ (calc.).Method H using 6-(4- methylphenyl)imi- dazo[2,1- b][1,3]thiazole-5-carbaldehyde a]pyrazin-8-one

Example 57:7-hydroxy-2-[(2,4-dichlorophenyl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method I Step 1

To a suspension of7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 2, 150 mg, 0.52 mmol) in DCE (10 mL) was added2,4-dichlorobenzaldehyde (101 mg, 0.58 mmol) and sodiumtriacetoxyborohydride (333 mg, 1.57 mmol). The resulting mixture wasstirred at room temperature for 18 h. The contents were treated with 1 NNaOH, added 10% Na₂CO₃ and extracted with CHCl₃ (3×). The organic layerswere combined, dried over Na₂SO₄, filtered and the solvent removed invacuo to give a residue which was purified by automated normal-phasechromatography (0-40% MeOH/DCM, silica gel) to give2-[(2,4-dichlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(166 mg, 0.373 mmol, 71% yield) as an off-white foam. MS, ES⁺ m/z 445.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64 (d, 1H) 7.55 (d, 1H)7.42-7.47 (m, 2H) 7.32-7.36 (m, 2H) 6.92-6.96 (m, 2H) 5.95 (s, 1H) 4.89(s, 2H) 3.92 (t, 2H) 3.76 (s, 3H) 3.71 (s, 2H) 3.59 (s, 2H) 2.85 (t, 2H)

Step 2

To a solution of2-[(2-chloro-4-fluorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(160 mg, 0.36 mmol) in EtOH (5 mL) was added 6 M HCl (3.27 mL, 19.6mmol). The resulting mixture was stirred at 100° C. for 3 h, thenallowed to reach room temperature with stirring overnight (forconvenience). The solvent was removed in vacuo and the residue wastriturated with Et2O (3×) and the triturants removed by decantation. Thesolid was dried under vacuum to give2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-onehydrochloride (121 mg, 0.33 mmol, 93% yield) as an off-white solid. MS,ES⁺ m/z 325.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.26 (br. s., 1H) 8.12 (s, 1H) 7.68 (d,1H) 7.63 (d, 1H) 7.49 (dd, 1H) 7.17 (s, 1H) 4.44 (t, 2H) 4.04 (br. s.,2H) 3.94 (br. s., 2H) 3.12 (br. s., 2H)

The following compounds 58-65 have been synthesized according to MethodI

Preparation Ex. Name Structure Analytical data Information 58 2-[(2-chlorophenyl)meth- yl]-7- hydroxy-3,4- dihydro-1H- pyrido[1,2-a]pyrazin-8-one

MS, ES⁺, 291.2 (M + H)⁺, ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.34 (br. s.,1 H) 8.17 (s, 1H) 7.68 (br. s., 1 H) 7.50-7.56 (m, 1 H) 7.38-7.45 (m, 2H) 7.24 (s, 1 H) 4.50 (br. s., 2 H) 4.19 (br. s., 2 H) 4.10 (br. s., 2H) 3.26 (br. s., 2 H) Method I using 2- chlorobenzaldehyde andIntermediate 2 59 2-[(2-chloro-6- fluoro- phenyl)methyl]- 7-hydroxy-3,4-dihydro-1H- pyrido[1,2- a]pyrazin-8-one

MS, ES⁺ 309.0 (M + H)⁺, ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.21 (br. s.,1 H) 8.07 (s, 1 H) 7.38-7.50 (m, 2 H) 7.27-7.33 (m, 1 H) 7.17 (s, 1 H)4.36 (t,, 2 H) 4.00 (s, 2 H) 3.90 (s, 2 H) 3.06 (br. s., 2 H) Method Iusing 2- chloro-4- fluorobenzaldehyde and Intermediate 2 60 2-[(2,6-dichlorophenyl) methyl]-7- hydroxy-3,4- dihydro-1H- pyrido[1,2-a]pyrazin-8-one

MS, ES⁺, 325.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.21 (br. s.,1 H) 8.06 (s, 1 H) 7.51-7.55 (m, 2 H) 7.37-7.43 (m, 1 H) 7.16 (s, 1 H)4.33 (t, 2 H) 4.00 (s, 2 H) 3.95 (s, 2 H) 3.06 (t, 2 H) Method I using2,6- dichlorobenzaldehyde and Intermediate 2 61 2-[(2-chloro-4-fluorophenyl)meth- yl)]-7- hydroxy-3,4- dihydro-1H- pyrido[1,2-a]pyrazin-8-one

MS, ES⁺, 309.0 (M + H)⁺, ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.09-11.38(m, 1 H) 8.10 (s, 1H) 7.61- 7.67 (m, 1 H) 7.51 (dd, 1 H) 7.29 (td, 1 H)7.15 (s, 1 H) 4.43 (t, 2 H) 4.02 (br. s., 2H) 3.91 (br. s., 2 H) 3.10(br. s., 2 H) Method I using 2- chloro-4- fluorobenzaldehyde andIntermediate 2 62 2-[(2,6- difluorophenyl) methyl]-7- hydroxy-3,4-dihydro-1H- pyrido[1,2- a]pyrazin-8-one

MS, ES⁺, 293.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.20 (br. s.,1 H) 8.06 (s, 1 H) 7.45-7.55 (m, 1 H) 7.12-7.22 (m, 3 H) 4.38 (t, 2 H)3.97 (s, 2 H) 3.88 (s, 2 H) 3.04 (br. s., 2 H) Method I using 2,6-difluorobenzaldehyde and Intermediate 2 63 2-[(4-bromo-2- chloro-phenyl)methyl]- 7-hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-onehydrochloride

MS, ES⁺, 368.9 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.16 (br. s.,1 H) 8.07 (s, 1 H) 7.78 (d, 1 H) 7.58-7.62 (m, 1 H) 7.49- 7.53 (m, 1 H)7.10 (s, 1 H) 4.40 (t, 2 H) 3.96 (s, 2 H) 3.83 (s, 2 H) 3.04 (br. s., 2H) Method I using 4- bromo-2- chlorobenzaldehyde and Intermediate 2 642-[(2-chloro-4- cyclopropyl- phenyl)methyl]- 7-hydroxy-3,4- dihydro-1H-pyrido[1,2- a]pyrazin-8-one hydrochloride

MS, ES⁺, 331.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.14 (br. s.,2 H) 8.06 (s, 1 H) 7.43 (d, 1 H) 7.21 (d, 1 H) 7.11 (s, 1 H) 7.07 (dd, 1H) 4.40 (br. s., 2 H) 3.99 (br. s., 2 H) 3.86 (br. s., 2 H) 3.06 (br.s., 2 H) 1.90-1.99 (m, 1 H) 0.95-1.01 (m, 2 H) 0.68- 0.74 (m, 2 H)Method I using 2- chloro-4- cyclopropylbenzalde- hyde and Intermediate 265 2-[(2- chlorophenyl)meth- yl]-7- hydroxy-3,3- dimethyl-1,4-dihydropyrido[1,2- a]pyrazin-8- one

MS, ES⁺, 319.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.28 (br. s.,1 H) 8.06 (s, 1 H) 7.63 (br. s., 1 H) 7.47 (d, 1 H) 7.31- 7.41 (m, 2 H)7.14 (s, 1 H) 4.30 (br. s., 2 H) 3.91 (br. s., 4 H) 1.22-1.31 (br. s., 6H) Method I using 2- chlorobenzaldehyde and Intermediate 11

Example 66:2-[(2,4-dichloro-5-nitro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

To a solution of2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Example 61, 30 mg, 0.083 mmol) in sulfuric acid (1 mL) was addedpotassium nitrate (16.8 mg, 0.17 mmol) in portions over 5 min. Theresulting mixture was stirred for 30 min at 0° C., then quenched byadding cold water (3 mL) followed by careful addition of sat'd. NaHCO₃.The aqueous phase was extracted with CHCl₃ (3×). The organic layers werecombined, dried over Na₂SO₄, filtered, and 0.5 mL 6N HCl was added tothe filtrate. The solvent was removed in vacuo to give to yield thehydrochloride salt of the title compound as a yellow solid (25 mg, 74%).MS, ES⁺, 370.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.19 (br. s., 1H) 8.22 (s, 1H)8.06-8.10 (m, 2H) 7.06 (s, 1H) 4.41 (br. s., 2H) 3.97 (br. s., 2H) 3.88(br. s., 2H) 3.05 (br. s., 2H)

Example 67:7-hydroxy-2-[1-(2-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method J

7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 2, 0.1 mmol, 0.1 mmol), 2′-methylacetophenone (14.8 mg,0.110 mmol), MP-BH₃CN (Sopachem, 80 mg, 0.199 mmol) were poured in amixture EtOH (0.6 mL): THF (0.3 mL): HOAc (0.1 mL) and stirred overnightat rt, then at 60° C. for 14 h. MP-BH₃CN (Sopachem, 40 mg, 0.050 mmol)and 2′-methylacetophenone (8 mg) was added. The mixture was heated at70° C. overnight. The reaction mixture was filtered, evaporated. Theresidue was purified by reverse phase chromatography to yield the PMBprotected intermediate (18 mg). This intermediate was dissolved in DCM(0.4 mL), TFA (0.4 mL) was added and the resulting mixture was stirredat rt for 30 min. The solvents were evaporated to yield the titlecompound as a brown oil (20 mg). High-Res MS, ES⁺, 285.1597 (M+H)⁺(obs.), 285.1603 (M+H)⁺ (calc.).

The following compounds 68-97 have been synthesized according to MethodsJ. Examples 94-97 were repurified by reverse phase chromatography.

Preparation Ex. Name R Analytical data Information 68 2-[1-(4-chlorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 305.1053 (M + H)⁺ (obs.), 3.05.1057 (M + H)⁺ (calc.).Method J using 4′- chloroaceto- phenone 69 2-[1-(2,5- dichlorophenyl)ethyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 399.0656 (M + H)⁺ (obs.), 339.0667 (M + H)⁺ (calc.).Method J using 2′,5′- dichloroaceto- phenone 70 7-hydroxy-2-{1- [4-(trifluoromethyl) phenyl]ethyl}- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 339.1321 (M + H)⁺ (obs.), 339.132 (M + H)⁺ (calc.).Method J using 4′- (trifluoromethyl) acetophenone 71 7-hydroxy-2-[1- (3-methylphenyl)eth- yl]-1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 285.1599 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.).Method J using 3′- methylaceto- phenone 72 2-[1-(3- chlorophenyl)eth-yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 305.1041 (M + H)⁺ (obs.), 3.05.1057 (M + H)⁺ (calc.).Method J using 3′- chloroaceto- phenone 73 2-(4-chloro-2,3- dihydro-1H-inden-1-yl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 317.1044 (M + H)⁺ (obs.), 317.1057 (M + H)⁺ (calc.).Method J using 4-chloro-1- indanone 74 2-[1-(2,6- dimethoxyphenyl)ethyl]-7- hydroxy- 1,2,3,4- tetrahdyro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 331.1638 (M + H)⁺ (obs.), 331.1658 (M + H)⁺ (calc.).Method J using 2′,6′- dimethoxyaceto- phenone 75 7-hydroxy-2-[1- (2,3,5-trifluorophenyl) ethyl]-1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 325.1161 (M + H)⁺ (obs.), 325.1164 (M + H)⁺ (calc.).Method J using 2′,3′,5′- trifluoroacetophe- none 76 2-[1-(2-chlorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 305.1039 (M + H)⁺ (obs.), 305.1057 (M + H)⁺ (calc.).Method J using 2- chloroacetophe- none 77 2-{1-[2- (benzyloxy)phe-nyl]-ethyl}-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 377.1847 (M + H)⁺ (obs.), 3.77.1865 (M + H)⁺ (calc.).Method J using 2′- benzyloxyacetophe- none 78 7-hydroxy-2-(1-phenylpentyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 313.1911 (M + H)⁺ (obs.), 313.1916 (M + H)⁺ (calc.).Method J using valerophenone 79 2-(7-fluoro-2,3- dihydro-1H-inden-1-yl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-

High-Res MS, ES⁺, 301.1338 (M + H)⁺ (obs.), 301.1352 (M + H)⁺ (calc.).Method J using 7-fluoro-1- indanone a]pyrazin-8-one 80 7-hydroxy-2-(2-phenyl-3,4- dihydro-2H- chromen-4-yl)- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

LCMS (Method D, ES⁺) RT, (M + H)⁺, 95% purity. Method J using flavanone81 2-[1-(3- fluorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 289.1344 (M + H)⁺ (obs.), 289.1352 (M + H)⁺ (calc.).Method J using 3′- fluoroacetophenone 82 2- cyclopentyl(phe-nyl)methyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-

High-Res MS, ES⁺, 325.1905 (M + H)⁺ (obs.), 325.1916 (M + H)⁺ (calc.).Method J using cyclopentyl phenyl ketone a]pyrazin-8-one 837-hydroxy-2-[1- (3- methoxyphenyl) ethyl]-1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 301.1534 (M + H)⁺ (obs.), 301.1552 (M + H)⁺ (calc.).Method J using 3′- methoxyacetophe- none 84 2-(2,3-dihydro-1H-inden-1-yl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 283.1427 (M + H)⁺ (obs.), 283.1447 (M + H)⁺ (calc.).Method J using 1-indanone 85 2-[1-(3-chloro- 2,6- difluorophenyl)ethyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 341.0881 (M + H)⁺ (obs.), 341.0868 (M + H)⁺ (calc.).Method J using 3′-chloro-2′,6′- difluoroacetophe- none 86 7-hydroxy-2-(6,7,8,9- tetrahydro-5H- benzo[7]annulen- 5-yl)-1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 311.1765 (M + H)⁺ (obs.), 311.1759 (M + H)⁺ (calc.).Method J using 1-benzosuberone 87 2-[1-(2,5- dimethylphenyl) ethyl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 299.1744 (M + H)⁺ (obs.), 2991.759 (M + H)⁺ (calc.).Method J using 2′,5′- dimethylacetophe- none 88 2-(1,2- diphenylethyl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 347.1757 (M + H)⁺ (obs.), 347.1759 (M + H)⁺ (calc.).Method J using deoxybenzoin 89 7-hydroxy-2-(1- phenylpropyl)- 1,2,3,4-tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 285.1589 (M + H)⁺ (obs.), 285.1603 (M + H)⁺ (calc.).Method J using propiophenone 90 7-hydroxy-2- (1,2,3,4- tetrahydronaph-thalen-1-yl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 297.1606 (M + H)⁺ (obs.), 297.1603 (M + H)⁺ (calc.).Method J using 1-tetralone 91 7-hydroxy-2-(7- methoxy- 1,2,3,4-tetrahydronaph- thalen-1-yl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 327.1693 (M + H)⁺ (obs.), 327.1709 (M + H)⁺ (calc.).Method J using 7-methoxy-1- tetralone 92 7-hydroxy-2-(4- methyl-2,3-dihydro-1H- inden-1-yl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

High-Res MS, ES⁺, 297.1601 (M + H)⁺ (obs.), 297.1603 (M + H)⁺ (calc.).Method J using 4-methyl-1- indanone 93 7-hydroxy-2-(1- phenylbutyl)-1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 299.1752 (M + H)⁺ (obs.), 299.1759 (M + H)⁺ (calc.).Method J using butyrophenone 94 4-[1-(7- hydroxy-8-oxo- 1,3,4,8-tetrahydro-2H- pyrido[1,2- a]pyrazin-2- yl)ethyl]benzoni- trile

High-Res MS, ES⁺, 296.1386 (M + H)⁺ (obs.), 296.1399 (M + H)⁺ (calc.)Method J using 4- acetylbenzonitrile 95 3-[1-(7- hydroxy-8-oxo- 1,3,4,8-tetrahydro-2H- pyrido[1,2- a]pyrazin-2- yl)ethyl]benzoni- trile

High-Res MS, ES⁺, 296.1383 (M + H)⁺ (obs.), 296.1399 (M + H)⁺ (calc.).Method J using 3- acetylbenzonitrile 96 N-{3-[1-(7- hydroxy-8-oxo-1,3,4,8- tetrahydro-2H- pyrido[1,2- a]pyrazin-2- yl)ethyl]phenyl}acetamide

High-Res MS, ES⁺, 328.1646 (M + H)⁺ (obs.), 328.1661 (M + H)⁺ (calc.)Method J using 3′- acetamidoacetophe- none 97 2-[1-(2,5- difluorophenyl)ethyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one

High-Res MS, ES⁺, 307.1252 (M + H)⁺ (obs.), 307.1258 (M + H)⁺ (calc.)Method J using 2′,5′- difluoroacetophe- none

Example 98:2-[1-(2-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method K Step1: Preparation of7-benzyloxy-2-[1-(2-fluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

5-benzyloxy-1-(2-chloroethyl)-2-(chloromethyl)pyridin-4-one(Intermediate 3, 0.32 mmol, 101 mg), sodium iodide (0.16 mmol, 24 mg,0.50 eq.), NEt₃ (4 eq., 1.32 mmol, 135 mg),(1-(2-fluorophenyl)ethanamine, 2.0 eq., 0.660 mmol) were placed in CH₃CN(2 mL). The reaction mixture was heated at 125° C. for 2.5 h. Additionof water (2 mL) and extraction with DCM (2 mL). The organic phase wasevaporated under vacuum and purified by reverse phase preparativechromatography to yield the title intermediate (101 mg as a yellow oil(83%). MS, ES⁺, 379.2 (M+H)⁺.

Step 2: Preparation of2-[1-(2-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

An aq. solution of HCl (2 mL, 5 N) was added to7-benzyloxy-2-[1-(2-fluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(101 mg, 0.27 mmol) and the mixture was heated for 2 h at 95° C. Themixture was then evaporated under vacuum. The residue was thentriturated with ether, filtered then dried under vacuum.

MS, ES⁺, 289.3 (M+H)⁺.

The following compounds 92-96 have been synthesized according to MethodsK

Preparation Ex. Name R Analytical data Information  99 2-[1-(4-fluorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin-8-one

MS, ES⁺, 289.2 (M + H)⁺, Method K using 1-(4- fluorophenyl)eth- anamine100 7-hydroxy-2-(2- hydroxy-1- phenylethyl)- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

MS, ES⁺ 287.2 (M + H)⁺, Method K using dl-2- phenylglycinol 1017-hydroxy-2- (2,2,2-trifluoro- 1-phenylethyl)- 1,2,3,4- tetrahydro-8H-pyrido[1,2- a]pyrazin-8-one

MS, ES⁺, 325.2 (M + H)⁺ Method K using 2,2,2-trifluoro-1- phenyl-ethylamine 102 7-hydroxy-2- [(2-phenyl-1,3- thiazol-4- yl)methyl]-1,2,3,4- tetrahydro-8H- pyrido[1,2-

MS, ES⁺, 340.3 (M + H)⁺, Method K using (2-phenyl-1,3- thiazol-4-yl)methylamine a]pyrazin-8-one 103 2-[(3,5- dimethyl-1- phenyl-1H-pyrazol-4- yl)methyl]-7- hydroxy- 1,2,3,4-

MS, ES⁺, 351.3 (M + H)⁺ Method K using c-(3,5-dimethyl- 1-phenyl-1h-pyrazol-4-yl)- methylamine tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one104 7-hydroxy-2-(1- phenylcyclopro- pyl)-3,4- dihydro-1H- pyrido[1,2-a]pyrazin-8-one

MS, ES⁺, 283.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.08 (br. s.,1 H) 7.99 (s, 1 H) 7.37-7.44 (m, 4 H) 7.30-7.36 (m, 1 H) 7.11 (s, 1 H)4.30 (t, 2 H) 3.88 (s, 2 H) 2.95-3.01 (m, Method K using 1-phenylcyclopropyl- amine 2 H) 1.03-1.08 (m, 2 H) 0.86-0.90 (m, 2 H) 1052-(2-fluoro-1- phenyl-ethyl)-7- hydroxy-3,4- dihydro-1H- pyrido[1,2-a]pyrazin-8-one

MS, ES⁺, 289.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 7.9 (s, 1H)7.44- 7.39 (m, 5H) 6.86 (s, 1H) 4.96-4.67 (m, 3H) 4.31-4.25 (m, 2H)4.02-3.80 (m, 2H) 3.01-2.86 (m, 2H) Method K using 2-fluoro-1- phenyl-ethylamine 106 2-[1-(2- chlorophenyl)cy- clopropyl]-7- hydroxy-3,4-dihydro-1H- pyrido[1,2- a]pyrazin-8-one

MS, ES⁺, 317.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 7.99 (s, 1 H)7.56 (dd, 1 H) 7.47-7.51 (m, 1 H) 7.34-7.43 (m, 2 H) 7.10 (s, 1 H) 4.29(t, 2 H) 3.95 (s, 2 H) 3.09 (t, 2 H) 1.18-1.22 Method K using 1-(2-chlorophenyl)cyclo- propylamine (m, 2 H) 0.94-0.99 (m, 2 H) 1072-(2,2-difluoro- 1-phenyl-ethyl)- 7-hydroxy-3,4- dihydro-1H- pyrido[1,2-a]pyrazin-8-one

MS, ES⁺, 307.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 7.9 (s, 1H)7.54- 7.40 (m, 5H) 7.33-7.08 (m, 1H) 6.87 (s, 1H) 6.83-6.54 (m, 1H)4.35-4.15 (m, 2H) 3.92 (quart., 2H) 3.11-3.03 Method K using2,2-difluoro-1- phenyl- ethylamine (m, 1H) 2.92-2.83 (m, 1H). 1082-(1,3- benzothiazol-2- yl)-7-hydroxy- 3,4-dihydro-1H- pyrido[1,2-a]pyrazin-8-one

MS, ES⁺, 300.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.27 (br. s.,1 H) 8.30 (s, 1 H) 7.87 (d, 1 H) 7.55 (d, 1 H) 7.42 (s, 1 H) 7.31-7.38(m, 1 H) 7.12- 7.18 (m, 1 H) 5.05 (s, 2 H) 4.66 (t, 2 H) 3.97-4.02 (m, 2H) Method K using 1,3-benzothiazol- 2-amine 109 7-hydroxy-2-(2-phenylcyclopro- pyl)-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one

MS, ES⁺, 283.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 8.03 (s, 1H)7.26- 7.24 (m, 2H) 7.20-7.17 (m, 3H) 7.06 (s, 1H) 4.38-4.30 (m, 2H)4.11-3.95 (m, 2H) 3.20-3.05 (m, 2H) 2.22 (s, 1H), 2.11-2.03 (m, 2H)1.17- 1.04 (m, 2H). Method K using 2- phenylcyclopropyl- amine 1107-hydroxy-2-(5- quinolyl)-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8- one

MS, ES⁺, 294.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.31 (br. s.,1 H) 9.20 (d, 1 H) 9.07 (d, 1 H) 8.28 (s, 1 H) 8.07 (d, 1 H) 7.97-8.04(m, 1 H) 7.92 (dd, 1 H) 7.53 (d, 1 H) 7.29 (s, 1 Method K using 5-aminoquinoline H) 4.67 (s, 4 H) 3.71 (d, 2 H) 111 7-hydroxy-2-(3-phenyloxetan- 3-yl)-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one

MS, ES⁺, 299.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 8.09 (s, 1H)7.81- 7.35 (m, 5H) 7.15 (s, 1H) 5.12 (br. s., 4H) 4.36 (t, 2H) 3.64 (s,2H) 2.70 (t, 2H). Method K using 3-phenyloxetan- 3-amine

Example 112:7-hydroxy-2-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of1-(2-anilinoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

A suspension of 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (100 mg, 0.43mmol) and N′-phenylethane-1,2-diamine (84.5 μL, 0.65 mmol) in water (2mL) was heated under microwave conditions at 150° C. for 90 min. Thesolvent was removed in vacuo and the residue treated with 10% Na₂CO₃ andCHCl₃ and passed through a phase separator tube. After removing theorganic solvent in vacuo, the residue was purified by automatednormal-phase chromatography (0-20% MeOH/DCM, 4 g silica gel cartridge).The product-containing fractions were combined and the solvent removedin vacuo to give1-(2-anilinoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one (58 mg,38% yield) as a tan solid. MS, ES⁺, 351 (M+H)⁺, ¹H NMR (400 MHz,DMSO-d₆) δ 7.49 (s, 1H), 7.31-7.40 (m, 5H), 7.08 (t, 2H, J=7.7 Hz),6.52-6.60 (m, 3H), 6.20 (s, 1H), 5.80 (t, 1H, J=6.1 Hz), 5.62 (t, 1H,J=5.7 Hz), 4.92 (s, 2H), 4.36 (d, 2H, J=5.8 Hz), 4.03 (t, 2H, J=6.2 Hz),3.38 (m, 2H).

Step 2: Preparation of7-benzyloxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

To a solution of1-(2-anilinoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one (55.mg,0.16 mmol) in DME (5 mL) and chloroform (100 mL) was added thionylchloride (500 μL, 6.9 mmol) in chloroform (100 mL) over 45 min atambient temperature. The contents were allowed to stir for 3 days (forconvenience), then 10 mL of 1M NaOH was added. The resulting mixture wasallowed to stir for 24 h at ambient temperature, then at 50° C. for 24h. The contents were transferred to a separatory funnel, the CHCl₃ layerremoved and the aqueous layer washed with CHCl₃ (2×). The organic layerswere combined, dried over MgSO₄, filtered and the solvent removed invacuo to give a residue which was purified by automated normal-phasechromatography (0-20% MeOH/DCM, 4 g silica gel cartridge). Theproduct-containing fractions were combined and the solvent removed invacuo to give7-benzyloxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (32 mg,61% yield) as a colorless glass. MS, ES⁺, 333 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 7.64 (s, 1H), 7.32-7.46 (m, 5H), 7.23-7.29 (m, 2H), 6.95 (d,2H, J=8.8 Hz), 6.80 (t, 1H, J=7.3 Hz), 6.22 (s, 1H), 4.99 (s, 2H), 4.38(s, 2H), 4.09-4.14 (m, 2H), 3.65 (t, 2H, J=5.6 Hz).

Step 3: Preparation of7-hydroxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (29.mg,0.090 mmol) was stirred in 6M HCl (2.mL, 12 mmol) at 100° C. for 2 h.The solvents were removed in vacuo to give7-hydroxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-onehydrochloride (24.5 mg, 0.089 mmol, 98% yield) as a brown solid. MS,ES⁺, 243 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H), 7.25-7.34 (m,4H), 6.99-7.03 (m, 2H), 6.84 (t, 1H, J=7.3 Hz), 4.68 (s, 2H), 4.51-4.56(m, 2H), 3.71-3.76 (m, 2H).

Example 113:7-hydroxy-2-(3-methylphenyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method L

Step 1: Preparation of7-benzyloxy-2-(o-tolyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneXantphos (45 mg, 0.078 mmol), Pd₂(dba)₃ (13 mg, 0.038 mmol) andpotassium tert-butoxide (0.135 g, 1.17 mmol) were added to a suspensionof 7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 1, 0.1 g, 0.39 mmol) and 3-bromotoluene (0.14 g, 0.78mmol) in 1,4-dioxane (1 mL). The mixture was heated at 130° C. for 14 h,then cooled to rt and filtered. The filtered solid was washed with EtOAcand the combined filtrates were evaporated under vacuum. The residue waspurified by chromatography (SiO₂, gradient from 100% DCM up to 7%methanolic ammonia in DCM) to yield the title intermediate as a yellowsolid (83 mg, 61%). MS, ES⁺, 347 (M+H)⁺.

Step 2: Preparation of7-hydroxy-2-(3-methylphenyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

An aq. solution of HCl (2 mL, 5 N) was added to7-benzyloxy-2-(m-tolyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (83mg, 0.24 mmol) and the mixture heated at 100° C. for 30 min., thencooled to rt. The reaction mixture was washed with CH₃Cl, treated withNorite®, filtered and evaporated to give a residue (30 mg, brown solid).Purification by reverse phase preparative chromatography yielded thetitle compound as a brown solid (22 mg, 24%). MS, ES⁺, 257 (M+H)⁺.

Example 114:7-hydroxy-2-[2-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound has been prepared according to Method L, but using1-bromo-2-(trifluoromethoxy)benzene. Purification of the intermediate bychromatography (SiO₂, gradient from 100% DCM up to 7% methanolic ammoniain DCM) yielded the intermediate as a yellow solid (127 mg) used in thenext step without any further purification. MS, ES⁺, 417.3 (M+H)⁺. HCltreatment (Method E) gave the title compound. MS, ES⁺, 327.2 (M+H)⁺. ¹HNMR (400 MHz, D₂O) δ 7.97 (s, 1H), 7.38 (m, 1H), 7.31 (t, 1H, J=7.6 Hz),7.19 (m, 2H), 7.08 (s, 0H), 4.50 (s, 2H), 4.43 (m, 2H), 3.65 (m, 2H).

Example 115:1,2-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of5-benzyloxy-2-(1-hydroxy-2-phenyl-ethyl)pyran-4-one

A solution of benzylmagnesium bromide (0.6 M, 1.2 eq., 10.4 mmol, 17.4mL) in THF was added dropwise (in ca. 20 min) to a solution of5-benzyloxy-4-oxo-pyran-2-carbaldehyde (Intermediate 4, 8.7 mmol, 2.0 g)in THF (20 mL) cooled at −70° C. The mixture was warmed to rt. Water wasadded, then the mixture was extracted with EtOAc. The combined organiclayers were dried over MgSO₄, filtered and concentrated under vacuum togive a brown oil (3.27 g). Purification by chromatography (SiO₂, 5%methanolic ammonia in DCM) gave the title intermediate (1.47 g, 52%).MS, ES⁺, 323.3 (M+H)⁺.

Step 2: Preparation of1-(2-aminoethyl)-5-benzyloxy-2-(1-hydroxy-2-phenyl-ethyl)pyridin-4-one

Ethylenediamine (13.7 mmol, 0.830 g, 3 eq.) was added to a solution of5-benzyloxy-2-(1-hydroxy-2-phenyl-ethyl)pyran-4-one (4.56 mmol, 1.47 g,1 eq.) in EtOH (5 mL) and the mixture was heated to 90° C. for 15.5 h.The reaction mixture was concentrated under vacuum. The residue wastaken up in a mixture of EtOAc/MeOH 90/10, washed with H₂O. The aqueouslayer was extracted with n-BuOH. The combined org. layers were driedover MgSO₄, filtered and concentrated to yield a brown oil (1.83 g,quant.) used in the next step without any further purification.

Step 3: Preparation of1-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Method M

SOCl₂ (15 mmol, 1.8 g, 3.1 eq.) was added to a solution of1-(2-aminoethyl)-5-benzyloxy-2-(1-hydroxy-2-phenyl-ethyl)pyridin-4-one(4.9 mmol, 1.8 g, 1.0 eq.) in DCM (10 mL). The mixture was stirred at rtfor 1 h. then evaporated under vacuum to yield a brown oil. This residuewas taken up in n-BuOH and an aq. solution of NaHCO₃ was added until thepH is 9. The mixture was then stirred for 14 h. at rt.

The reaction mixture was decanted, and the aq. layer was extracted withn-BuOH. The org, phase was dried over MgSO₄, filtered and concentratedto yield a black oil (1.5 g). Purification by chromatography (SiO₂, 10%methanolic ammonia in DCM) yielded the title intermediate as a brown oil(0.7 g) MS, ES⁺, 347.3 (M+H)⁺.

Step 4: Preparation of1,2-dibenzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Method N

Benzaldehyde (0.58 mmol, 0.061 g, 2.0 eq.) and molecular sieve 4A (<5μm, 0.3 g) were added to a solution of1-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (0.29mmol, 0.1 g, 1.0 eq.) in MeOH (4 mL). The mixture was stirred 1 h at rt,then HOAc (0.58 mmol, 0.035 g, 2.0 eq.) followed by sodiumcyanoborohydride (0.87 mmol, 0.054 g, 3.0 eq.). The mixture was thenstirred 14 h at rt. The mixture was filtered and concentrated. Theresidue was taken up in DCM, washed with H2O then dried over MgSO₄,filtered and concentrated under vacuum to give a residue. Purificationby chromatography (SiO₂, from 3% methanolic ammonia up to 10% in DCM)yielded the title intermediate (30 mg). MS, ES⁺, 337.4 (M+H)+

Step 5: Preparation of:1,2-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

An aq. solution of HCl (2 mL, 5 N) was added to a solution of1,2-dibenzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(0.034 mmol, 0.015 g, 1.0 eq.) in dioxane (1 mL). The mixture wasstirred at 90° C. for 1 h then cooled to rt. The reaction mixture waswashed with CHCl₃ (2×2 mL). The aq. phase was filtered on Celite, thenconcentrated under vacuum to give a brown solid. Purification by reversephase preparative chromatography yielded the title compound (9 mg).High-Res MS, ES⁺, 347.1764 (M+H)⁺ (obs.), 347.1759 (M+H)⁺ (calc.).

Example 116:2-benzyl-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 5-benzyloxy-2-[hydroxy(phenyl)methyl]pyran-4-one

Method O

A solution of phenylmagnesium chloride (2 M in THF, 6.53 mL, 13.0 mmol,1.5 eq.) was added dropwise to a cold (−70° C.) solution of5-benzyloxy-4-oxo-pyran-2-carbaldehyde (Intermediate 4, 8.7 mmol, 2.0 g,1.0 eq.) in THF (20 mL). The mixture was stirred and the temperatureallowed to warm up to −30° C. H₂O was then added (10 mL), the mixtureallowed to reach rt. The mixture was extracted with EtOAc. The combinedorg. layers were washed with H₂O, then dried over MgSO₄, filtered andevaporated to give an oil (4.0 g). This residue was triturated with Et₂Oand the precipitate formed filtered to yield the title intermediate(1.44 g, 54%) used in the next step without any further purification.MS, ES⁺, 309.2 (M+H)⁺.

Step 2: Preparation of1-(2-aminoethyl)-5-benzyloxy-2-[hydroxy(phenyl)methyl]pyridin-4-one

Method P

Ethylenediamine (0.84 g, 3 eq.) and5-benzyloxy-2-[hydroxy(phenyl)methyl]pyran-4-one (4.61 mmol, 1.42 g, 1.0eq.) were heated at 70° C. for 4 h. The mixture was cooled to rt,concentrated and the residue was purified by chromatography (SiO₂, 10%methanolic ammonia in DCM) to yield the title intermediate as a brownoil (0.9 g, 60%). MS, ES⁺, 351.3 (M+H)⁺.

Step 3: Preparation of7-benzyloxy-1-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A, using1-(2-aminoethyl)-5-benzyloxy-2-[hydroxy(phenyl)methyl]pyridin-4-one (0.9g, 2.6 mmol) and longer reaction time (heated 48 h at 60° C.).

The residue obtained was dissolved in MeOH (12 mL) and sodiumborohydride (100 mg, 3 mmol) were added and the mixture stirred at rtfor 1 h. Another portion of sodium borohydride (100 mg) were added andthe mixture stirred at rt for 14 h. The reaction mixture wasconcentrated to give a residue (700 mg). Purification by chromatography(SiO₂, 10% methanolic ammonia in DCM) yielded the title intermediate(417 mg). MS, ES⁺, 333.3 (M+H)⁺.

Step 4: Preparation of2-benzyl-7-benzyloxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Method Q

7-benzyloxy-1-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (0.42mmol, 140 mg), potassium carbonate (0.87 mmol, 121 mg, 2.05 eq.), sodiumiodide (ca. 1 mg) and benzyl bromide (0.35 mmol, 59 mg, 0.8 eq.,dissolved in CH₃CN 1 mL) were stirred 14 h at rt in CH₃CN (1.5 mL). ThenDMF (2 mL) were added and the resulting reaction mixture stirred another14 h at rt.

H₂O was then added, the mixture was extracted with EtOAc. The combinedorg. layers were washed with H₂O, then dried over MgSO₄, filtered andevaporated to give a residue (100 mg). Purification by chromatography(SiO₂, gradient from DCM up to 10% methanolic ammonia in DCM) yieldedthe title intermediate (120 mg). MS, ES⁺, 423.3 (M+H)⁺.

Step 5: Preparation of2-benzyl-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

An aq. solution of HCl (3 mL, 5 N) was added to2-benzyl-7-benzyloxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(0.28 mmol, 120 mg) and the mixture heated at 90° C. for 2 h, thencooled to rt. The precipitate was filtered, washed with Et₂O, driedunder vacuum to yield the title compound (62 mg) High-Res MS, ES⁺,333.1613 (M+H)⁺ (obs.), 333.1603 (M+H)⁺ (calc.).

Example 117:2-(2,6-dichlorobenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to method Q, but using2,6-dichlorobenzyl bromide.

High-Res MS, ES⁺, 401.0815 (M+H)⁺ (obs.), 401.0823 (M+H)⁺ (calc.).

Example 118:(1R)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate (240 mg) was prepared according to Method N,using 7-benzyloxy-1-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(200 mg, 0.60 mmol), 4-ethylbenzyldehyde (205 mg, 1.5 mmol, 2.5. eq.)and Si—BH₃CN (Silicycle, 1.5 g, 1.3 mmol, 2.2 eq.). MS, ES⁺, 451.3(M+H)⁺.

Step 2: Preparation of(1R)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(240 mg) was purified by chiral chromatography (SFC conditions onChiralCel OD (50×266 mm, 360 mL/min, 25° C., CO₂+40% EtOH, conc: 20 g/),to give 100 mg of the first eluting enantiomer (RT 7.13 min) as a brownoil, attributed to(1R)-2-[(4-ethylphenyl)methyl]-7-hydroxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneand 110 mg of the second eluting enantiomer, attributed to(1S)-2-[(4-ethylphenyl)methyl]-7-hydroxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(RT 11.5 min) as a brown oil. ChiralCel OD-H, 50% EtOH in n-heptane (5um, 240×4.6 mm, 1.0 mL/min) RT 6.4 min (100% purity). ChiralCel OD-H,50% EtOH in n-heptane (5 um, 240×4.6 mm, 1.0 mL/min) RT 10.2 min (100%purity).

(1R)-2-[(4-ethylphenyl)methyl]-7-hydroxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(100 mg, 0.22 mmol) was reacted following Method E to yield the titlecompound (25 mg). High-Res MS, ES⁺, 361.1903 (M+H)⁺ (obs.), 361.1916(M+H)⁺ (calc.).

Example 119:(1S)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

(1S)-2-[(4-ethylphenyl)methyl]-7-hydroxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(100 mg, 0.22 mmol) was reacted following Method E to yield the titlecompound (31 mg, 38%). High-Res MS, ES⁺, 361.1933 (M+H)⁺ (obs.),361.1916 (M+H)⁺ (calc.).

Example 120:2-(4-ethylbenzyl)-7-hydroxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of tert-butyl7-benzyloxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate

Di-tert-butyl dicarbonate (258 mg, 1.5 eq., 1.2 mmol) was added to asuspension of 7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(200 mg, 0.78 mmol) and DMAP (0.1 eq., 0.078 mmol) in THF (10 mL) andthe reaction mixture was stirred 2 days at rt. H₂O was added, themixture was extracted with EtOAc. The combined org. layers were washedwith H₂O, then dried over MgSO₄, filtered and evaporated. The residuewas purified by reverse phase chromatography to yield the titleintermediate (100 mg). MS, ES⁺), 357.1 (M+H)⁺.

Step 2: Preparation of tert-butyl7-benzyloxy-1-isopropyl-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate

sec-butyllithium (1.2 eq., 0.33 mmol, 1.4 M, 0.240 mL) was addeddropwise to a cold (−78° C.) solution of tert-butyl7-benzyloxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate(100 mg, 0.28 mmol) in anhydrous THF (5 mL) and the resulting reactionmixture was stirred 30 min at −78° C. 2-iodopropane (143 mg, 3 eq., 0.84mmol) was then added dropwise and the mixture was allowed to reach rtand stirred for 14 h. An aq. solution of NaHCO₃ was added and themixture extracted with EtOAc. The combined org. phases were dried overMgSO₄, filtered and evaporated under vacuum to give a yellow oil (80mg). The residue was purified by reverse phase chromatography to yieldthe title intermediate (20 mg). MS, ES⁺, 399.2 (M+H)⁺.

Step 3: Preparation of7-benzyloxy-1-isopropyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

TFA (3 mL) was added to a solution of tert-butyl7-benzyloxy-1-isopropyl-8-oxo-3,4-dihydro-H-pyrido[1,2-a]pyrazine-2-carboxylate(300 mg, 0.75 mmol) in DCM (3 mL). The mixture was stirred at rt for 2h. The solvents were evaporated to yield the title intermediate as abrown oil (350 mg) used in the next step without further purification.MS, ES⁺, 299.1 (M+H)⁺.

Step 4: Preparation of7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-isopropyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method C using7-benzyloxy-1-isopropyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one and4-ethylbenzaldehyde. The crude product was purified by reverse phasechromatography (SiO2, DCM-MeOH—NH₄OH 97-2.7-0.3) to yield the titleintermediate as a yellow oil (57%).

Step 5: Preparation of2-(4-ethylbenzyl)-7-hydroxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E, using7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-isopropyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one,affording the title compound as a yellow solid MS, ES⁺), 327 (M+H)⁺.

Example 121:2-(2,6-dimethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-2-[(2,6-dimethylphenyl)methyl]-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method F using7-benzyloxy-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one and2,6-dimethylbenzaldehyde (Intermediate 5), reaction at 40° C. for 40 h.The crude product was purified by chromatography (SiO₂, gradient from100% DCM up to 6% methanolic ammonia in DCM) to give the titleintermediate as a colorless oil (60 mg). MS, ES⁺, 389.3 (M+H)⁺.

Step 2: Preparation of2-(2,6-dimethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E from7-benzyloxy-2-[(2,6-dimethylphenyl)methyl]-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneto give the title compound as a yellow solid.

MS, ES⁺, 299.27 (M+H)⁺.

Example 122:2-(4-ethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method F using7-benzyloxy-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 5) and 4-ethylbenzaldehyde (quant.) followed by Method Eusing7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one.

MS, ES⁺, 299.2 (M+H)⁺.

Example 123:1-(4-fluorophenyl)-7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of5-benzyloxy-2-[(4-fluorophenyl)-hydroxy-methyl]pyran-4-one

The title intermediate was prepared according to Method O using4-fluorophenylmagnesium bromide. MS, ES⁺, 327.2 (M+H)⁺.

Step 2: Preparation of1-(2-aminoethyl)-5-benzyloxy-2-[(4-fluorophenyl)-hydroxy-methyl]pyridin-4-one

The title intermediate was prepared according to Method P using5-benzyloxy-2-[(4-fluorophenyl)-hydroxy-methyl]pyran-4-one as a brownoil. MS, ES⁺, 369.3 (M+H)⁺.

Step 3: Preparation of7-benzyloxy-1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using1-(2-aminoethyl)-5-benzyloxy-2-[(4-fluorophenyl)-hydroxy-methyl]pyridin-4-oneas a brown oil. MS, ES⁺, 349.3 (M+H)⁺.

Step 4: Preparation of7-benzyloxy-1-(4-fluorophenyl)-2-(8-quinolylmethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using7-benzyloxy-1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-oneand quinoline-8-carbaldehyde as a yellow oil. MS, ES⁺, 492.3 (M+H)⁺.

Step 5: Preparation of1-(4-fluorophenyl)-7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E from7-benzyloxy-1-(4-fluorophenyl)-2-(8-quinolylmethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneto give the title compound as an orange solid.

MS, ES⁺, 402.3 (M+H)⁺.

Example 124:2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-2-[(2,6-dimethylphenyl)methyl]-1-(4-fluorophenyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using7-benzyloxy-1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-oneand 2,6-dimethylbenzaldehyde. MS, ES⁺, 469.3 (M+H)⁺,

Step 2: Preparation of2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using7-benzyloxy-2-[(2,6-dimethylphenyl)methyl]-1-(4-fluorophenyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(57%). MS, ES⁺, 379.3 (M+H)⁺.

Example 125:2-(4-ethylbenzyl)-7-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-tetrahydropyran-4-yl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using7-benzyloxy-1-tetrahydropyran-4-yl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 6) as a white solid (65%). MS, ES⁺, 459.4 (M+H)⁺.

Step 2: Preparation of2-(4-ethylbenzyl)-7-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-tetrahydropyran-4-yl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneas a pale yellow solid (93%).

MS, ES⁺, 369.32 (M+H)⁺.

Example 126:2-(4-ethylbenzyl)-7-hydroxy-1-[3-(pyridin-3-yl)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step1: Preparation of5-benzyloxy-2-[(3-bromophenyl)-hydroxy-methyl]pyran-4-one

I₂ (ca. 5 mg) was added to a suspension of magnesium (26.1 mmol, 633 mg,1.2 eq.) in anhydrous THF (5 mL). A solution of 1,3-dibromobenzene (26.1mmol, 6.33 g, 1.2 eq.) in THF (10 mL) was added dropwise. The mixturewas stirred at rt for 3 h then 1 h at reflux.

This solution was added dropwise onto a solution of5-benzyloxy-4-oxo-pyran-2-carbaldehyde (21.7 mmol, 5.0 g, 1.0 eq.) inTHF (100 mL) and the mixture was stirred 1 h at rt. An aq. solution ofHCl (20 mL, 1 N) was added. The resulting reaction mixture was extractedwith EtOAc. The combined org. layers were dried over MgSO₄, filtered andevaporated to give a residue (13 g).

Purification by chromatography (SiO₂, DCM-MeOH—NH₄OH 98-1.8-0.2) yieldedthe title intermediate (1.3 g). MS, ES⁺, 487.2 (M+H)⁺.

Step 2: Preparation of1-(2-aminoethyl)-5-benzyloxy-2-[(3-bromophenyl)-hydroxy-methyl]pyridin-4-one

Ethylenediamine (5.1 mmol, 0.3 g, 1.5 eq.) was added to a solution of5-benzyloxy-2-[(3-bromophenyl)-hydroxy-methyl]pyran-4-one (3.4 mmol, 1.3g) in EtOH (10 mL). The mixture was stirred at 40° C. for 48 h. Thesolvent was evaporated under vacuum to give a residue used in the nextstep without any further purification. MS, ES⁺, 429.2/431.2 (M+H)⁺.

Step 3: Preparation of7-benzyloxy-1-(3-bromophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using1-(2-aminoethyl)-5-benzyloxy-2-[(3-bromophenyl)-hydroxy-methyl]pyridin-4-one,involving a purification by reverse phase chromatography.

Step 4: Preparation of7-benzyloxy-1-(3-bromophenyl)-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using7-benzyloxy-1-(3-bromophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(43%) involving a purification by chromatography (SiO2, gradient fromDCM up to 10% methanolic ammonia in DCM). MS, ES⁺, 529.2/531.2 (M+H)⁺.

Step 5: Preparation of7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-[3-(3-pyridyl)phenyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-1-(3-bromophenyl)-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(0.19 mmol, 100 mg), pyridine-3-boronic acid (0.23 mmol, 29 mg, 1.2eq.), cesium carbonate (2.29 mmol, 745 mg) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.009mmol, 7 mg, 0.05 eq.) were placed in a mixture 10:1 dioxane:H₂O (2 mL).The mixture was degassed then heated 3 h at 100° C. The reaction mixturewas then cooled to rt. H₂O was added and the mixture extracted withEtOAc. The combined org. layers were washed with a sat. solution ofNaCl, dried over MgSO₄, filtered and evaporated to give a residue (100mg). Purification by chromatography (SiO₂, gradient from DCM up to 10%methanolic ammonia) yielded the title intermediate as a brown oil (89mg, 89%). MS, ES⁺, 528.2 (M+H)⁺.

Step 6: Preparation of2-(4-ethylbenzyl)-7-hydroxy-1-[3-(pyridin-3-yl)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-[3-(3-pyridyl)phenyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneas a pale yellow solid.

MS, ES⁺, 438.2 (M+H)⁺.

Example 127:2-benzyl-7-hydroxy-3-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of2-benzyl-7-benzyloxy-3-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method Q using7-benzyloxy-3-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 7) and benzyl bromide as a yellow oil. MS, ES⁺, 423.3(M+H)⁺.

Step 2: Preparation of2-benzyl-7-hydroxy-3-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using of2-benzyl-7-benzyloxy-3-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(26%). High-Res MS, ES⁺, 333.1604 (M+H)+(obs.), 333.1603 (M+H)⁺ (calc.).

Example 128:2,3-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of2,3-dibenzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 8) and benzaldehyde involving a purification of the crudeproduct by chromatography (SiO₂, gradient from DCM up to 10% methanolicammonia in DCM) (48%). MS, ES⁺, 437.3 (M+H)⁺.

Step 2: Preparation of2,3-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using2,3-dibenzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as anorange solid (quant.). High-Res MS, ES⁺, 347.175 (M+H)⁺ (obs.), 347.1759(M+H)⁺ (calc.).

Example 129:3-benzyl-2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of3-benzyl-7-benzyloxy-2-[(2,6-dichlorophenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 8) and 2,6-dichlorobenzaldehyde involving a purificationof the crude product by chromatography (SiO₂, gradient from DCM up to10% methanolic ammonia in DCM) as a colorless oil. MS, ES⁺, 505.3(M+H)⁺.

Step 2: Preparation of3-benzyl-2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using3-benzyl-7-benzyloxy-2-[(2,6-dichlorophenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(18%). High-Res MS, ES⁺, 415.0984 (M+H)⁺ (obs.), 415.098 (M+H)⁺ (calc.).

Example 130:7-hydroxy-3-methyl-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-3-methyl-2-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using7-benzyloxy-3-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 9) and 4-(trifluoromethoxy)benzaldehyde involving apurification of the crude product by chromatography (SiO₂, gradient fromDCM up to 10% methanolic ammonia in DCM) as a colorless oil (61%). MS,ES⁺, 445.3 (M+H)⁺.

Step 2: Preparation of7-hydroxy-3-methyl-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using7-benzyloxy-3-methyl-2-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneas a light yellow solid (66%).

High-Res MS, ES⁺, 355.1269 (M+H)⁺ (obs.), 355.127 (M+H)⁺ (calc.).

Example 131:2-benzyl-7-hydroxy-3-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of2-benzyl-7-benzyloxy-3-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using7-benzyloxy-3-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one(Intermediate 9) and benzaldehyde involving a purification of the crudeproduct by chromatography (SiO₂, gradient from DCM up to 10% methanolicammonia in DCM) as a colorless oil (90%). MS, ES⁺, 361.3 (M+H)⁺.

Step 2: Preparation of2-benzyl-7-hydroxy-3-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using2-benzyl-7-benzyloxy-3-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneas a light yellow solid (71%).

High-Res MS, ES⁺, 271.1454 (M+H)⁺ (obs.), 271.1447 (M+H)⁺ (calc.).

Example 132:2-benzyl-7-hydroxy-3-(2-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of5-benzyloxy-2-(chloromethyl)-1-(2-chloro-4-phenyl-butyl)pyridin-4-one

The title intermediate was prepared according to Method C using1-amino-4-phenylbutan-2-ol involving a purification of the crude productby chromatography (SiO₂, gradient from DCM up to 15% methanolic ammoniain DCM) as a yellow oil. MS, ES⁺, 380.3 (M+H)⁺.

Step 2: Preparation of5-benzyloxy-2-(chloromethyl)-1-(2-chloro-4-phenyl-butyl)pyridin-4-one

The title intermediate was prepared according to Method B using5-benzyloxy-2-(chloromethyl)-1-(2-chloro-4-phenyl-butyl)pyridin-4-one at60° C. as a dark beige powder used in the next step without any furtherpurification. MS, ES⁺, 416.1/418.1 (M+H)⁺.

Step 3: Preparation of2-benzyl-7-benzyloxy-3-phenethyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method K using5-benzyloxy-2-(chloromethyl)-1-(2-chloro-4-phenyl-butyl)pyridin-4-one,benzylamine and triethylamine, involving a purification of the crudeproduct by chromatography (SiO₂, gradient from DCM up to 15% methanolicammonia in DCM) as a dark yellow oil. MS, ES⁺, 451.2 (M+H)⁺.

Step 4: Preparation of:2-benzyl-7-hydroxy-3-(2-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using2-benzyl-7-benzyloxy-3-phenethyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneas a yellow solid (42%).

High-Res MS, ES⁺, 361.1907 (M+H)⁺ (obs.), 361.1916 (M+H)⁺ (calc.).

Example 133:9-chloro-2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-9-chloro-2-[(2-chloro-6-fluoro-phenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-2-[(2-chloro-6-fluoro-phenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Intermediate prepared for the Example 7, 63 mg, 0.16 mmol) andN-chlorosuccinimide (22 mg, 0.16 mmol) were poured in CH₃CN (1 mL). Thesolution was degassed for 2 min, then heated overnight at 50° C. DCM (1mL) was added and the suspension filtered on a 5 um filter. The solventwas evaporated to yield a light yellow oil (45 mg) used in the next stepwithout any further purification. MS, ES⁺, 433.2/435.2 (M+H)⁺.

Step 2: Preparation of9-chloro-2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using7-benzyloxy-9-chloro-2-[(2-chloro-6-fluoro-phenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneas an off white powder (quant.).

High-Res MS, ES⁺, 343.0398 (M+H)⁺ (obs.), 343.0416 (M+H)⁺ (calc.).

Example 134:6-fluoro-7-hydroxy-2-[[2-chlorophenyl]methyl]-3,4-dihydro-1H-pyrido[l,2-a]pyrazin-8-one

Step 1: Preparation of 6-bromo-2-fluoropyridin-3-ol

To a stirring solution of 2-fluoropyridin-3-ol (8.00 g, 70.7 mmol) inacetic acid (70 mL), potassium acetate (4.25 g, 70.7 mmol) was added.The solution was cooled to 0° C. after the potassium acetate haddissolved. Bromine (3.65 mL, 70.7 mmol) in acetic acid (10 mL) was addeddropwise and the resulting mixture was stirred at room temperature for 1h. Sodium sulfite (5 g) was added, followed by 1 N NaOH (30 mL). Afterthe brown color of the solution disappeared, the solution was extractedwith EtOAc (2×100 mL). The EtOAc extracts were combined, washed withwater (100 mL), saturated NaHCO₃ (100 mL), brine (100 mL), dried overNa₂SO₄, filtered and the solvent removed in vacuo to give a residuewhich was purified by automated normal-phase chromatography (0-40%EtOAc/heptane) to give 6-bromo-2-fluoropyridin-3-ol (8.80 g, 45.8 mmol,65% yield) as a white solid. MS (ES⁺) m/z 191.9 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 7.24-7.34 (m, 2H), 5.75 (br. s., 1H).

Step 2: Preparation of 6-bromo-2-fluoro-3-methoxypyridine

To a stirring solution of 6-bromo-2-fluoropyridin-3-ol (8.80 g, 45.8mmol) in acetone (150 mL), potassium carbonate (12.67 g, 91.67 mmol) andiodomethane (5.71 mL, 91.7 mmol) were added. The resulting mixture wasstirred under reflux overnight. The contents were filtered and thesolvent removed in vacuo to give a residue which was purified byautomated normal-phase chromatography (0-30% EtOAc/heptane) to give6-bromo-2-fluoro-3-methoxypyridine (7.00 g, 34.0 mmol, 74% yield) as awhite solid. MS (ES⁺) m/z 206.0 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 7.27-7.34 (m, 1H), 7.20 (dd, 1H), 3.88-3.95(m, 3H).

Step 3: Preparation of 6-bromo-2-fluoro-3-methoxypyridin-4-ol

To a stirring solution of 6-bromo-2-fluoro-3-methoxypyridine (2.70 g,13.1 mmol) in THF (50 mL) at −78° C., LDA (2 M in THF, 7.86 mL, 15.7mmol) was added slowly. The resulting mixture was stirred at −78° C. for1 h, then trimethyl borate (1.75 mL, 15.7 mmol) was added portionwise.The resulting mixture was stirred at −78° C. for 1 h then allowed toreach room temperature with stirring over 1 h. Hydrogen peroxide (30%,2.49 mL, 15.7 mmol) was added slowly to the contents, and the resultingmixture was stirred at room temperature for 1 h. Sodium sulfite (5 g)was added, followed by water (50 mL) and 1 N HCl (50 mL) and stirringcontinued for 1 h. The contents were extracted with EtOAc (2×150 mL).The EtOAc extracts were combined, washed with brine (200 mL), dried overNa₂SO₄, filtered and the solvent removed in vacuo to give an off-whitesolid, which was used without further purification.

Step 4: Preparation of 4-benzyloxy-6-bromo-2-fluoro-3-methoxypyridine

To a stirring solution of crude 6-bromo-2-fluoro-3-methoxypyridin-4-ol(2.91 g, 13.1 mmol) in acetonitrile (50 mL), benzyl bromide (1.87 mL,15.7 mmol) and potassium carbonate (3.98 g, 28.8 mmol) were added andthe resulting mixture stirred at reflux overnight. After cooling to roomtemperature, the contents were filtered and washed with EtOAc. Thefiltrate was concentrated in vacuo to give a residue which was purifiedby automated normal-phase chromatography (0-20% EtOAc/heptane) to give4-benzyloxy-6-bromo-2-fluoro-3-methoxy-pyridine (3.22 g, 10.3 mmol, 79%yield, two steps) as a white solid. MS (ES⁺) m/z 312.0 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 7.36-7.49 (m, 5H), 6.96-7.02 (m, 1H), 5.19(s, 2H), 3.88-3.96 (m, 3H).

Step 5: Preparation of4-benzyloxy-6-fluoro-5-methoxypyridine-2-carbaldehyde

To a stirring solution of 4-benzyloxy-6-bromo-2-fluoro-3-methoxypyridine(4.10 g, 13.1 mmol) in Et₂O (60 mL) at −78° C., nBuLi (1.6 M in hexanes,9.85 mL, 15.8 mmol) was added dropwise. After the resulting mixture wasstirred at −78° C. for 40 min, DMF (1.52 mL, 19.7 mmol) was added andstirring continued for 2 h at −78° C. Saturated NH₄Cl (50 mL) was addedand the resulting mixture extracted with EtOAc (2×150 mL). The EtOAcextracts were combined. washed with water (100 mL), brine (100 mL),dried over Na₂SO₄, filtered and the solvent removed in vacuo to give aresidue which was purified by automated normal-phase chromatography(0-30% EtOAc/heptane) to give4-benzyloxy-6-fluoro-5-methoxypyridine-2-carbaldehyde (1.85 g, 7.06mmol, 54% yield) as an off-white solid. MS (ES⁺) m/z 262.0 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 9.77-9.84 (m, 1H), 7.52-7.58 (m, 1H),7.35-7.49 (m, 5H), 5.22-5.30 (m, 2H), 4.03-4.10 (m, 3H).

Step 6: Preparation of2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methylamino]ethanol

To a stirring solution of4-benzyloxy-6-fluoro-5-methoxypyridine-2-carbaldehyde (1.85 g, 7.06mmol) in MeOH (30 mL) at room temperature was added ethanolamine (0.52g, 8.47 mmol). The contents were stirred at room temperature for 30 min,then NaBH₄ (0.40 g, 10.6 mmol) was added. After stirring 1 h, thereaction was complete and the solvent was removed in vacuo. Ethylacetate (150 mL) was added then washed with 0.1 N NaOH (20 mL), brine(20 mL), dried over Na₂SO₄, filtered and the solvent removed in vacuo togive 2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methylamino]ethanol(1.75 g, 5.71 mmol, 81% yield) as a colorless oil which was used withoutfurther purification.

Step 7: Preparation of tert-butylN-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl]-N-(2-hydroxyethyl)carbamate

To a stirring solution of2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methylamino]ethanol (2.16g, 7.06 mmol) in DCM (50 mL), was added triethylamine (1.96 mL, 14.1mmol), followed by di-tert-butydicarbonate (2.00.g, 9.18 mmol). Theresulting mixture was stirred at room temperature overnight, dilutedwith DCM (30 mL) and washed with 1 N HCl (2×30 mL), brine (20 mL), driedover Na₂SO₄, filtered and the solvent removed in vacuo to give a residuewhich was purified by automated normal-phase chromatography (0-60%EtOAc/heptane) to give tert-butylN-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl]-N-(2-hydroxyethyl)carbamate(2.32 g, 5.72 mmol, 81% yield) as a colorless oil. MS (ES⁺) m/z 407.2[M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 7.33-7.46 (m, 5H), 6.69-6.90 (m, 1H), 5.20(br. s., 2H), 4.32 (d, 2H), 3.93 (d, 3H), 3.78 (br. s., 2H), 3.46-3.55(m, 2H).

Step 8: Preparation of2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl-tert-butoxycarbonyl-amino]ethylMethanesulfonate

To a stirring solution of tert-butylN-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl]-N-(2-hydroxyethyl)carbamate(2.32 g, 5.71 mmol) in DCM (50 mL) at 0° C. was added triethylamine(1.19 mL, 8.56 mmol) and methanesulfonyl chloride (0.53 mL, 6.85 mmol).The resulting mixture was stirred at 0° C. for 1 h, diluted with DCM (20mL) and washed with 1 N HCl (3×20 mL), water (5 mL), brine (10 mL),dried over Na₂SO₄, filtered and the solvent removed in vacuo to give2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl-tert-butoxycarbonyl-amino]ethylmethanesulfonate (2.63 g, 5.43 mmol, 95% yield) as a colorless oil whichwas used without further purification.

Step 9: Preparation of2-[tert-butoxycarbonyl-[(6-fluoro-4-hydroxy-5-methoxy-2-pyridyl)methyl]amino]ethylMethanesulfonate

To a stirring solution of2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl-tert-butoxycarbonyl-amino]ethylmethanesulfonate (2.63 g, 5.43 mmol) in EtOAc (60 mL), was added 10%Pd/C (1.5 g, 1.42 mmol). After purging under vacuum, the contents werereacted for 2 h under H₂ at atmospheric pressure. The contents werefiltered and the solvent removed in vacuo to give a residue which wasused without further purification. MS (ES⁺) m/z 395.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.75 (s, 1H), 4.25-4.32 (s, 3H),3.73-3.78 (s, 3H), 3.48-3.58 (m, 4H), 3.14-3.18 (m, 2H), 2.31-2.37 (m,9H).

Step 10: Preparation of tert-butyl6-fluoro-7-methoxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate

To a stirring solution of2-[tert-butoxycarbonyl-[(6-fluoro-4-hydroxy-5-methoxy-2-pyridyl)methyl]amino]ethylmethanesulfonate (2.10 g, 5.32 mmol) in acetonitrile (30 mL), was addedpotassium carbonate (1.10 g, 7.99 mmol). The resulting mixture wasstirred at room temperature overnight, diluted with ethyl acetate (60mL), filtered through a pad of Celite and the solvent removed in vacuoto give a residue which was purified by automated normal-phasechromatography (0-5% MeOH/DCM) to give tert-butyl6-fluoro-7-methoxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate(1.60 g, 5.36 mmol, 100% yield) as a colorless oil. MS (ES⁺) m/z 299.2[M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 6.29 (s, 1H), 4.51 (s, 2H), 4.02-4.10 (m,2H), 3.92-3.98 (m, 3H), 3.77-3.86 (m, 2H), 1.51 (s, 9H).

Step 11: Preparation of6-fluoro-7-methoxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

To a stirring solution of tert-butyl6-fluoro-7-methoxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate(1.61 g, 5.40 mmol) in DCM (25 mL) was added TFA (25.mL). The resultingmixture was stirred at room temperature for 1 h and the solvent removedin vacuo to give6-fluoro-7-methoxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-onetrifluoroacetate as a colorless oil which was used without furtherpurification.

Method R Step 12a: Preparation of2-[(2-chlorophenyl)methyl]-6-fluoro-7-methoxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

To a stirring solution of6-fluoro-7-methoxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-onetrifluoroacetate (290 mg, 0.58 mmol) in DCM (5 mL) was added2-chlorobenzaldehyde (80 μL, 0.69 mmol) and two drops of acetic acid,followed by sodium triacetoxyborohydride (244 mg, 1.15 mmol). Theresulting mixture was stirred at room temperature overnight, dilutedwith DCM (20 mL), washed with saturated NaHCO₃ (3×20 mL), brine (20 mL),dried over Na₂SO₄, filtered the solvent removed in vacuo to give aresidue which was purified by automated normal-phase chromatography(0-5% MeOH/DCM) to give2-[(2-chlorophenyl)methyl]-6-fluoro-7-methoxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(83.0 mg, 0.257 mmol, 45% yield) as colorless oil. MS (ES⁺) m/z 323.0[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.46-7.59 (m, 2H), 7.34-7.43 (m, 2H),6.89 (s, 1H), 4.28 (br. s., 2H), 3.96 (s, 2H), 3.87 (s, 2H), 3.01-3.11(m, 2H).

Step 12b: Preparation of2-[(2-chlorophenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

To a stirring solution of2-[(2-chlorophenyl)methyl]-6-fluoro-7-methoxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(78 mg, 0.24 mmol) in DCM (10 mL) at 0° C., was slowly added borontribromide (1 M in DCM, 0.97 mL, 0.97 mmol). The resulting mixture wasstirred at 0° C. for 1 h, allowed to reach room temperature and stirredfor 3 h, then quenched with the addition of MeOH (3 mL). The solvent wasremoved in vacuo and the residue which was purified by automatednormal-phase chromatography [0-10% (5% HOAc in MeOH)/DCM] to give thepurified free base, was converted to its HCl salt by treating with HCl(2 M in Et2O, 20 mL) and evaporated to dryness under vacuum to give2-[(2-chlorophenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-onehydrochloride (65.0 mg, 0.188 mmol, 78% yield) as a pale purple solid.MS (ES⁺) m/z 309.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.52 (dd, 3H), 7.44-7.49 (m, 1H),7.29-7.40 (m, 2H), 6.02 (s, 1H), 3.94 (t, 2H), 3.71-3.77 (m, 5H), 3.62(s, 2H), 2.89 (t, 2H).

Example 135:2-[(4-(trifluoromethoxy)phenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method R using6-fluoro-7-methoxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-onetrifluoroacetate and 4-(trifluoromethoxy)benzaldehyde, followed bydemethylation with BBr₃ to give2-[(4-(trifluoromethoxy)phenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-onehydrochloride (53%). MS, ES⁺, 359.0 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.54-7.70 (m, 2H), 7.32-7.49 (m, 2H),6.98 (s, 1H), 4.41 (br. s., 2H), 4.13-4.30 (m, 4H), 3.35 (br. s., 2H).

Example 136:9-chloro-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-9-chloro-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-chlorosuccinimide (1 equiv., 0.2670 mmol, 37.14 mg) was added to asolution of7-benzyloxy-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Intermediate prepared for the Example 13, 100 mg, 0.27 mmol) in CH₃CN(1 mL). The mixture was degassed and stirred 14 h at 50° C. The reactionmixture was allowed to cool to rt. The precipitate was filtered and thefiltrates were evaporated to give the title intermediate as a brown oil(113 mg) used in the next step without further purification. MS, ES⁺,409.3 (M+H)⁺.

Step 2: Preparation of9-chloro-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using7-benzyloxy-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(63%).

MS, ES⁺, 319 (M+H)⁺.

Example 137:9-chloro-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of9-chloro-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-chlorosuccinimide (68.2 mg, 0.511 mmol) was added to a solution of2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Intermediate prepared for the Example 58, 200 mg, 0.487 mmol) in CH₃CN(1 mL). The mixture was degassed and stirred 1 h at room temperature.The contents were poured into brine, extracted with DCM, dried overNa₂SO₄, filtered and the solvent removed in vacuo to give a residuewhich was purified by normal-phase chromatography to give the titleintermediate as a yellow oil (50 mg). MS, ES⁺, 446.3 (M+H)⁺.

Step 2: Preparation of9-chloro-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using9-chloro-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(30%).

MS, ES⁺, 326.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.54-7.60 (m, 1H), 7.45-7.53 (m, 2H),7.32-7.44 (m, 2H), 4.07 (t, 2H), 3.92 (s, 2H), 3.82 (s, 2H), 2.97 (br.s., 2H)

Example 138:9-bromo-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-9-bromo-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-bromosuccinimide (428 mg, 1 eq., 2.4 mmol) was added to a solution of7-benzyloxy-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Intermediate prepared for the Example 13, 900 mg, 2.4 mmol) in CH₃CN (3mL) and the mixture was stirred 1 h at 40° C. An aq. solution of NaHCO₃was added and the mixture was extracted with DCM. The combined organiclayers were dried over MgSO₄, filtered and evaporated to give a yellowoil (1.2 g). Purification by chromatography (SiO₂, DCM-MeOH—NH₄OH97-2.7-0.3) to yield the title intermediate as a yellow solid (86%). MS,ES⁺, 451.3/453.2 (M+H)⁺.

Step 2: Preparation of9-bromo-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using7-benzyloxy-9-bromo-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneas a yellow solid (94%). MS, ES⁺, 363.2 (M+H)⁺.

Example 139:9-bromo-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of9-bromo-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-bromosuccinimide (0.91 g, 5.11 mmol) was added to a solution of2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Intermediate prepared for the Example 58, 200 mg, 0.487 mmol) in CHCl₃(75 mL). The mixture was stirred 1 h at room temperature. The contentswere poured into brine, extracted with DCM, dried over Na₂SO₄, filteredand the solvent removed in vacuo to give a residue which was purified bynormal-phase chromatography to give the title intermediate as a yellowsolid (1.5 g). MS, ES⁺, 490.0 (M+H)⁺.

Step 2: Preparation of9-bromo-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using9-bromo-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(80%).

MS, ES⁺, 370.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.49-7.63 (m, 3H), 7.40 (dd, 2H),4.09-4.21 (m, 2H), 4.03 (s, 2H), 3.91 (s, 2H), 3.08 (d, 2H)

Example 140:2-[(2-chlorophenyl)methyl]-7-hydroxy-9-iodo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of2-[(2-chlorophenyl)methyl]-9-iodo-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-iodosuccinimide (152 mg, 0.678 mmol) was added to a solution of2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Intermediate prepared for the Example 58, 265 mg, 0.645 mmol) in HOAc(5 mL). The solvent was removed in vacuo to give a residue which waspurified by normal-phase chromatography to give the title intermediateas a yellow solid (155 mg). MS, ES⁺, 537.3 (M+H)⁺.

Step 2: Preparation of2-[(2-chlorophenyl)methyl]-7-hydroxy-9-iodo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using2-[(2-chlorophenyl)methyl]-9-iodo-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(74%).

MS, ES⁺, 417.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.75 (br. s., 2H), 7.41-7.63 (m, 3H),4.28-4.44 (m, 4H), 4.14 (br. s., 2H), 3.32 (br. s., 2H)

Example 141:9-cyclopropyl-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of7-benzyloxy-9-cyclopropyl-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-9-bromo-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Intermediate formed for the preparation of Example 120, 100 mg, 0.22mmol), cyclopropylboronic acid (5 eq., 1.10 mmol, 99.7 mg),[bis(diphenylphosphino)ferrocene]dichloropalladium (II) (3 eq., 0.66mmol, 484 mg) and cesium carbonate (0.5 eq., 0.110 mmol, 35.9 mg) wereplaced in a mixture 1,4-dioxane (3 mL) and H₂O (1 mL). The mixture wasdegassed for 10 min. then heated 20 min. at 110° C. under microwaveirradiation followed by 14 h at 100° C. (oil bath). The solvents wereevaporated and the residue purified by chromatography (SiO₂, gradientfrom EtOAc up to 20% methanolic ammonia in EtOAc) to yield the titleintermediate (30 mg, 33%). MS, ES⁺, 415.4 (M+H)⁺.

Step 2: Preparation of9-cyclopropyl-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using7-benzyloxy-9-cyclopropyl-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(69%).

MS, ES⁺, 325.3 (M+H)⁺.

Example 142:2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

9-bromo-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one(Intermediate prepared for Example 139, 100 mg, 0.204 mmol),cyclopropylboronic acid (26.3 mg, 0.306 mmol), palladium (II) acetate(4.6 mg, 0.02 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25.4mg, 0.04 mmol) and cesium carbonate (200 mg, 0.61 mmol) were suspendedin 1,4-dioxane (4 mL). The mixture was degassed for 10 min. then heated18 h at 95° C. The solvents were evaporated and the residue purified byto give the title intermediate as a colorless oil. MS, ES⁺, 451.3(M+H)⁺.

Step 2: Preparation of2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-oneand the crude product purified by HPLC (5%). MS, ES⁺, 331.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.90 (s, 1H), 7.48-7.64 (m, 2H), 7.38(dd, 2H), 7.34-7.45 (m, 2H), 4.31-4.51 (m, 2H), 4.07 (s, 2H), 3.85-4.00(m, 2H), 3.00 (d, 2H), 1.46-1.62 (m, 1H), 0.89-1.07 (m, 2H), 0.57-0.74(m, 2H)

REFERENCES

-   Apud, J. A. and D. R. Weinberger (2007). “Treatment of cognitive    deficits associated with schizophrenia—Potential role of    catechol-O-methyltransferase inhibitors.” CNS Drugs 21(7): 535-557.-   Bonifacio, M. J., P. N. Palma et al. (2007).    “Catechol-O-methyltransferase and its inhibitors in Parkinson's    disease.” CNS Drug Reviews 13(3): 352-379.-   Borchardt, R. T., D. R. Thakker et al. (1976). “Catechol    0-Methyltransferase 0.8. Structure-Activity-Relationships for    Inhibition by 8-Hydroxyquinolines.” Journal of Medicinal Chemistry    19(4): 558-560.-   Ciliax, B. J., C. Heilman et al. (1995). “The Dopamine    Transporter—Immunochemical Characterization and Localization in    Brain.” Journal of Neuroscience 15(3): 1714-1723.-   Fatemi, S. H. and T. D. Folsom (2009). “The Neurodevelopmental    Hypothesis of Schizophrenia, Revisited.” Schizophrenia Bulletin    35(3): 528-548.-   Goldman-Rakic, P. S., S. A. Castner et al. (2004). “Targeting the    dopamine D-1 receptor in schizophrenia: insights for cognitive    dysfunction.” Psychopharmacology 174(1): 3-16.-   Howes, O. D. and S. Kapur (2009). “The Dopamine Hypothesis of    Schizophrenia: Version III—The Final Common Pathway.” Schizophrenia    Bulletin 35(3): 549-562.-   Lin Y. et al. (2012), “Detecting S-adenosyl-1-methionine-induced    conformational change of a histone methyltransferase using a    homogeneous time-resolved fluorescence-based binding assay”    Analytical Biochemistry, 423(1): 171-177.Kaenmaki, M., A. Tammimaki    et al. (2010). “Quantitative role of COMT in dopamine clearance in    the prefrontal cortex of freely moving mice.” J Neurochem. 114(6):    1745-1755.-   Lachman, H. M., D. F. Papolos et al. (1996). “Human    catechol-O-methyltransferase pharmacogenetics: Description of a    functional polymorphism and its potential application to    neuropsychiatric disorders.” Pharmacogenetics 6(3): 243-250.-   Learmonth, D. A., L. E. Kiss et al. (2010). “The Chemistry of    Catechol 0-Methyltransferase Inhibitors.” Basic Aspects of    Catechol-O-Methyltransferase and the Clinical Applications of Its    Inhibitors 95: 119-162.-   Marenco, S. and D. R. Weinberger (2000). “The neurodevelopmental    hypothesis of schizophrenia: Following a trail of evidence from    cradle to grave.” Development and Psychopathology 12(3): 501-527.-   Nutt, J. G. and J. H. Fellman (1984). “Pharmacokinetics of    Levodopa.” Clinical Neuropharmacology 7(1): 35-49.-   Nutt, J. G., W. R. Woodward et al. (1985). “The Effect of Carbidopa    on the Pharmacokinetics of Intravenously Administered Levodopa—the    Mechanism of Action in the Treatment of Parkinsonism.” Annals of    Neurology 18(5): 537-543.-   Olanow, C. W. and P. B. Watkins (2007). “Tolcapone.” Clinical    Neuropharmacology 30(5): 287-294.-   Pickard, B. (2011). “Progress in defining the biological causes of    schizophrenia.” Expert Reviews in Molecular Medicine 13.-   Russ, H., et al. (1999). “Detection of tolcapone in the    cerebrospinal fluid of Parkinsonian subjects.” Naunyn-Schmiedeberg's    Archives of Pharmacology 360(6): 719-720.-   Yavich, L, M. M. Forsberg et al. (2007). “Site-specific role of    catechol-O-methyltransferase in dopamine overflow within prefrontal    cortex and dorsal striatum.” Journal of Neuroscience 27(38):    10196-10202.

1. A compound of formula I, or a pharmaceutically acceptable saltthereof:

wherein: X is selected from hydrogen; chloro; bromo, iodo andcyclopropyl; Z is selected from hydrogen and fluoro; R₁ and R₂ are eachindependently selected from hydrogen; C₁₋₄ alkyl; aryl; substitutedaryl; arylalkyl and heterocycle; R₃ and R₄ are each independentlyselected from hydrogen; C₁-C₄ alkyl; aryl and arylalkyl; R₅ is selectedfrom aryl, heteroaryl, heterocycle, C₁-C₁₀ alkyl or C₁-C₁₀ cycloaklyl,optionally substituted with one or more groups selected from hydrogen;mono-, di-, or trihalomethyl; C₁-C₄ alkyl; C₃-C₁₀ cycloalkyl; halo;heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and NHC(O)R,wherein R is C₁-C₄ alkyl; and Y is (CR₆R₇)_(n), wherein n is from 0-3,and R₆ and R₇ are independently selected from hydrogen; C₁-C₆ alkyl;C₃-C₅ cycloalkyl; C₁-C₄ alkylhydroxyl; mono- di-, or trihaloalkyl; andaryl; R₆ and R₇ may also come together to form a C₃-C₆ cycloalkyl; orwhen R₅ is phenyl, one of R₆ or R₇ comes together with R₅ to form abicycle